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1. Introduction
Biobank acts as a library for genotypic and phenotypic data for a variety of biological samples. It is the process of acquiring, storing, processing, and distributing biological materials for the purpose of clinical use, including for the development of precision medicine. The term biobanking covers a broad range of samples, including those of animal, plant, and microbial origins. For instance, animal samples can be organ tissue, marrow, and synovial fluid, while plants can be roots, leaves, bark, flowers, and lastly microbial samples. The biobanking arena has seen significant advances from collecting and cataloging samples to having detailed archives of genotypic and phenotypic information. The storing of this information is part of the newest wave in biobanking, virtual biobanking. Virtual biobanks contain full genomes of previously collected specimen that may be accessed through specialized software or portals. Virtual biobanking assists investigators in searching multiple sites for specimen worldwide, essentially, allowing for the mining of data remotely [1]. Integration of genomics, proteomics, and metabolomics, as well as introduction of highly sensitive analysis methods, has translated into a demand for high-quality specimens and the need for accurate, reliable, and standardized clinical data. However, current methods in collecting samples are strenuous, expensive, and unreliable. Samples collected in the field have to be chilled or frozen until analysis, but the shipping of large chilled containers and powering freezers are cost limitations affecting research projects. Furthermore, there is a relatively small window of time between sample collection, storage, and analysis to preserve sample integrity; reducing the reliability of data. As a result, there has been a growing demand in the market for developing ambient temperature storage methods. In the following sections, the relevance of biobanking to precision medicine will be discussed as well as advances in sample collection and ambient temperature storage methods to reduce the cost of acquiring and storing precious biospecimen.
2. Precision medicine
In the last decade, there has been a push to understand factors that affect an individual’s health on the molecular level. These factors include an individual’s unique lifestyle and environment because it is now understood that epigenetics plays a large role in a person’s health as well as their development of chronic diseases, such as cancer [2]. Epigenetics and its effects on multiple “omics” (e.g., proteomics) require more than a snapshot of a single person’s life. Instead, large data sets ranging from local population (i.e., a neighborhood or city block) to a statewide population, or larger, are required to truly understand the connection between lifestyle and health; but this is not the only advantage of having a large sample size. Determining treatment for a disease requires the largest possible sample size, in order to account for all the possible variables that lead to developing the illness. The marriage of genetic sequencing and external factors that affect health (i.e., lifestyle and environmental) is the foundation of precision medicine. Precision medicine is the use of multiple facets of an individual’s health to develop a unique treatment plan [3] (Figure 1). With the cost of sequencing decreasing, it has become possible to query the whole genome in search of variants that are known to cause certain disease, and, thus, develop targeted therapies and reduce the overall strain placed on the body [4, 5]. Analysis of the human genome in the context of diagnostic medicine is one of the main facets of precision medicine. The current methodology for designing treatment plans is based on general information obtained from clinical trials; however, every person is unique and there are numerous instances where these “umbrella” treatment methods prove to be unsuccessful [3]. Thus, by being able to determine the root cause of the disease, be it lifestyle affecting gene expression, genetic inheritance of a mutation, or a random mutation itself, precision medicine provides the opportunity to have a focused approach in diagnostic medicine.
Figure 1.
Precision medicine is a holistic approach to treatment where for the first time, the phenotypic, proteomic, metabolomic, and the genomic composition of the individual as well as their links to other factors such as the microbiome and even the environment will be taken into consideration. This means treating the patient as a “whole” in contrast with the current isolated symptom-treatment approach. The goal of precision medicine is to develop a personalized treatment regimen, a one-of-a-kind approach that would have a better clinical outcome for the patient.
Precision medicine, and the initiative to push it forward, was strongly endorsed by the Obama administration after a young woman was able to determine the cause of her extremely unusual form of liver cancer through virtual searches of sequenced genomes of donors with the same disease [6]. The synergy between genetic markers and new therapies for cancer treatment is one powerful example of precision medicine. Typically, biopsied tissue samples or whole blood samples are used as the material for sequencing [6, 7]. For example, liquid biopsies are now routinely used for the analysis of cell-free DNA to look for progression/regression of cancer as well as additional genomic mutations [8]. As technology advances, instant interdisciplinary integration has become a reality and bioinformatic biobanking makes this integration possible [4]. However, there are many instances when hospitals or research facilities will not release the sequenced data of the samples that were collected or preserved specimens, and literature sources have inadequate information of the biospecimen used [6, 8]. This increases the necessity to have both a national and global data base available so that invaluable information could be accessed seamlessly. One of the first steps in creating such a large data bank is the development of the Million Donor cohort.
Precision medicines’ Million Donor cohort comes with a great responsibility for those institutions preserving these samples to answer future research questions [8]. The purpose of the cohort is to begin collecting data from one million individuals across the nation with diverse backgrounds [3, 9]. Building such a large cohort proves to be a daunting task; however, Terry [6] has shown that, when able to, patients will take the initiative to be active members in their health maintenance. Although questionnaires will be used to develop the cohort data, the success of precision medicine depends on the number of available electronic medical records (EMRs) to gain valuable insight into quantitative medical data [3]. Developing such a sample pool that can be easily accessed requires storing the data in virtual biobanks, a topic that will be discussed in detail later in the chapter [9, 10]. Biobanking and the accessibility of data with a user-friendly network for the purpose of data mining are crucial not only to both short-term and long-term goals of the Precision Medicine Initiative but also to the future. Access to samples is necessary to fulfill the vision of combining established clinicopathological parameters with emerging molecular profiling approaches to create diagnostic, prognostic, and therapeutic solutions that are precisely tailored to an individual patient’s unique requirements. Sample availability and sample preservation via biobanking are key to the future of the Precision Medicine Initiative and beyond.
3. Biobanking
In this section, the growth of biobanking for the purpose of current research interests will be discussed. Biobanking has been implemented in the scientific community for over 100 years by various institutions worldwide [11, 12]. Biobanks are large repertoires of biospecimen, ranging from animal samples to plant and microbes, that are used for research purposes [12]. Biobanking itself is a relatively simple concept (Figure 2). All types of biospecimen are stored in a biobank for long, yet finite amounts of time. These repositories of specimen in traditional biobanks remain in large freezers and other storage facilities until needed [12, 13]. Thus, biobanks are extremely valuable for translational research studies since generations of specimen may be stored and received.
Figure 2.
Infrastructure needed to biobank samples in a laboratory (left to right). Blood, buccal swab, or tissue biopsy/aspirate samples collected from donors are transported to the research facility if the collection site is remote to the sample processing laboratory. Maintaining traceability and transparency should be mandatory to all human samples, the samples are cataloged electronically when received and connected with the donor’s electronic health record (EHR) if available, along with other relevant information before either biobanking or processing the sample for nucleic acid or other biomolecule (DNA, RNA, buffy coat, proteins) extraction. Depending on the size of the donor pool, the most efficient means of processing the large cohort of samples is by automation. The biomolecule extracted is analyzed for quantity and quality before storage in a biobank at −80, or −196°C (liquid nitrogen). Consequently, for an economical means of storage of a large cohort of samples, the extracted biomolecules can be stored in a chemistry matrix for dry state or “glassy state” such as RNA/DNA stable (Biomatrica), RNAsecure (ThermoFisher) or GenTegra RNA/DNA (GenTegra LLC) or on treated paper such as Whatman FTA or GenSaver or untreated paper such as Whatman 903 or GenCollect. The choice of media for storage for biobanking is institute dependent.
Standardization of samples is key to successful biobanking. Reliability of samples collected in an ethical and legal manner with the oversight of the Institutional Review Board (IRB) or equivalent ethics committee for the biobanking institutions in their respective countries is crucial to ensuring reproducibility of results. International standards are being established by both the European Union [14] and International Society of Biological and Environmental Repositories (ISBER) in the United States [15] to establish standardization metrics for biobanked samples. ISBER coordinated the launch of the International Repository Locator (IRL) website in early 2015. This centralized locator, analogous to a “repository directory,” was created to increase the profile of individual repositories including ISBER, researchers, funding bodies, governments, and private industry. However, not all facilities with biobanks are willing or able to share these invaluable biospecimens [3, 12, 13]. With such limitations on the use of biobanks, the importance to develop new methods for biobanking continues to grow as technology and research methods have advanced and become more refined to solve previously, seemingly impossible medical mysteries. The Million Donor cohort acts as one solution to the problem of free-data sharing since the project’s purpose is to create a comprehensive virtual biobank for the purpose of precision medicine and bettering healthcare [3, 16]. Making biobanking a realistic tool and more accessible requires the blending of specimen collection and analysis.
To streamline biobanking and research analysis, a new concept in biobanking is bioinformatic biobanking. This refers to the querying of sequenced genomes that have been stored in virtual biobanks. Bioinformatic biobanks are large databases of information pertaining to the sequenced and analyzed specimen [12, 17]. In this concept of a biobank, an individual’s immutable genetic markers form a library to be queried over a lifetime for continuing patient management. Once a sample is analyzed and the data stored, it is then a simple matter of querying the data when and as required for specific gene regions, biomarkers, variations, etc. This approach is currently being implemented by Helix personal genomics with whole genome sequencing as the first step. Using this method negates the need for long-term sample storage because the whole genome can be virtually analyzed for specific biomarkers that may correlate with a disease. Once the genomic analysis is completed, any future test queries involve only a bioinformatic search, as opposed to additional sample collection and repeated analysis. This reduces the cost of biomedical research significantly; however, the collection, transportation, and storage of samples until analysis occurs still pose a significant cost and slow efforts in developing a globally available virtual biobank. In the next section, the sample types used for biobanking will be discussed, and advances that will eliminate the cost of storing and shipping such liquid samples.
3.1 Sample types used for biobanking
The most common sample types collected for precision medicine and biobanking of human specimen are tissue samples and whole blood. Tissue samples can be further subdivided into liquid biopsy samples for circulating tumor cells (CTC), tissue biopsy samples such as formalin-fixed paraffin-embedded (FFPE) tissue, and fresh frozen tissue samples or wet mount tissue slides. Whole blood samples can be: peripheral blood mononuclear cells (PBMCs), serum, or plasma. Additional, albeit less common, sample types collected are cerebrospinal fluid (CSF), urine, and fecal material. When collecting these samples, it will be imperative to have “True Control” samples from surrounding disease-free tissue and corresponding known disease-state samples for comparisons; but, it is not always practical for tissue biopsy samples or CSF. In such instances “external” matched controls must serve as acceptable substitutes for “True Control” samples.
3.1.1 Tissue
Tissue samples such as formalin-fixed paraffin-embedded (FFPE) blocks have been stored since the early twentieth century. FFPE tissue samples are a common sample type collected from biopsies. Although core biopsy samples yield a healthy amount of tissue, tissue biopsy procedure is a painful process for the patient and can potentially cause considerable trauma to the surrounding tissue. Fine needle aspirate (FNA) biopsy with a 21-gauge needle to remove tissue samples for pathology is less traumatic to the patient and to the surrounding tissue. Compared to core biopsy samples that are typically about 17 mg or more, the FNA samples are just 2–10 mg and the amount of sample that is donated to research is often less than 1 mm as priority for testing of the biopsy sample is to perform cytopathology. The best outcome for nucleic acid-based testing from tissue samples is to isolate nucleic acid from fresh or flash-frozen at −196°C tissue samples. There is no ambient temperature method available to preserve tissue samples for extracting good-quality nucleic acid.
FFPE is the most common method of preserving tissue samples at ambient temperature. FFPE tissue storage has been used for three decades [18] as a means of keeping tissue samples at ambient temperature for future research [19, 20]. This has created a large resource of pathologically interesting human and animal samples. Fixing tissue samples with formalin and embedding in paraffin preserves the pathology of the tissue. But formalin fixation can cause both inter and intra protein cross-linking [21, 22, 23] as well as cross-linking of histones to DNA [24]. Other factors affecting the quality of nucleic acid from FFPE samples include buffering formalin, time and temperature of fixation and penetration of formalin into the tissue by stasis, or by ultrasound, or microwave irradiation. The nucleic acid and protein quality are additionally dependent on the time of collection of tissue following postmortem interval and cold ischemia. Acceptable time for collection of tissue samples is between 4 h postmortem and 12 h after cold ischemia has set in. Acceptable time for formalin fixation of tissue postmortem is <48 h for RNA [25, 26], <24 h for proteins [27, 28, 29, 30, 31, 32], and <72 h for DNA [33, 34, 35, 36]. It would be best to isolate the nucleic acids from FFPE samples within the acceptable time to ensure the best outcome for the quality of the nucleic acid isolated. The isolated nucleic acid can be further stored at ambient temperature by removing the aqueous media from the nucleic acid sample or by adding some commercially available stabilizers for ambient temperature storage of nucleic acid. Although cross-linking of nucleic acid is of concern with aged FFPE samples [18, 33], nucleic acid extracted from FFPE samples have been successfully used for amplification, single cell analysis, and methylation studies. Decalcification of the FFPE sample using EDTA allows for longer PCR product [37], stronger fluorescence in situ hybridization (FISH) signals, lower background staining [38], and superior comparative genomic hybridization [1] results as compared to other methods.
3.1.2 Blood and blood components
Perhaps the most economical samples are blood samples collected in EDTA tubes [35]. A host of specialized blood collection tubes are commercially available for stabilization of transcripts such as Tempus Blood RNA tubes and PAXgene Blood RNA tubes [39]. The strategy for storing the samples for short-term usage and long-term biobanking needs will determine the quality of the sample. Acceptable short-term storage of weeks to months of blood and blood components such as serum, plasma, peripheral mononuclear cells (PBMCs) etc. is at 4 to −20°C and long-term storage is at −80 to −196°C. Liquid samples such as whole blood, saliva, plasma, and serum samples as dried spots can be stored for decades at ambient temperature if sampled on chemically treated substrate such as FTA or GenSaver paper cards [40, 41].
Serum and plasma samples can be stored at ambient temperature for extended periods of time on chemically treated bead matrix such as GenTegra LLC’s Matrix Chaperone (MC) (Figure 3). Up to 250 μL of serum or plasma sample can be applied to the MC for storage and for biobanking. Downstream analysis of the MC can be performed simply by adding back equivalent volume of water to the MC. The full complement of analytes, proteins, enzymes, and nucleic acid in serum and clotting factors in plasma samples (data not shown) have been successfully stored for 25 days at ambient temperature on MC consisting of a randomly packed chemically treated microsphere wafer when compared to pristine always frozen at −20°C serum samples (Table 1).
Figure 3.
Ambient storage of serum samples. It is possible to store the entire complement of biological molecules in serum (or any other biological fluids) on a simply made storage device consisting of 2-μm polystyrene beads coated with stabilization chemistry collectively called matrix chaperone (MC) for ambient storage and transportation. The collection device was a simple three-component device (i), containing a cap (A) with the resuspended stabilization chemistry in a matrix of polystyrene beads and the holding chamber (B) with silica gel (C) to facilitate drying. A volume of 250 μL of serum sample was added to the cap containing the chemical matrix of polystyrene beads (iib) and capped. The assembly was placed in an upside-down position for at least 12 h to facilitate drying. To initiate analysis, the sample was reconstituted with 250 μL of water (iic). The sample is recovered by transferring the sample to a 1.5-mL tube (iid) and centrifuging the sample at maximum speed for a minute (iie). A complete metabolic panel and a lipid panel test were performed on this reconstituted serum sample (Table 1).
Table 1.
Stability of serum enzymes, proteins, lipids, and metabolites at ambient when stored on the polystyrene bead matrix, MC, containing ambient stabilization chemistry for all biomolecules. A volume of 250 μL of CAP-certified serum samples spotted on the polystyrene matrix (MC) tubes and dried before storing for 25 days at ambient. Corresponding control serum samples were stored at −20°C. After 25 days of storage at ambient, the experimental and control samples were hydrated with 250 μL of water. All the analytes from the rehydrated MC serum samples and the fresh always frozen −20°C control samples were quantified for the complete metabolic panel and the lipid panel with the cobas® 6000 analyzer. The percent recovery of the analytes was calculated for the ambient stored samples compared to the control serum samples from the initial raw values of the test biomolecules. International units per liter (IU/L) of the enzyme panel for alanine amino transferase (ALT), aspartate aminotransferase (AST), enzyme marker creatine phosphokinase (CK), amylase, and gamma glutamyl transferase (GGT) are within the normal range for the ambient stored serum samples when compared to −20°C control samples. The level of the alkaline phosphatase (ALP) was low compared to the control serum samples indicating that the stabilizer is not able to protect the labile ALP enzyme. All the molecules tested in the protein panel and the lipid panel were in the normal range and maintained at between 68% and 83% of control indicating stability at ambient of all biomolecules in this panel on the MC. Of the three metabolites tested in the metabolic panel, the stabilizing matrix of the serum sample stored at ambient could not stabilize the metabolite creatine but cortisol and testosterone were stabilized. Normal ranges for panel values were taken from http://www.mayoclinic.org/ (April 3, 2013) except for the testosterone normal range, which was taken from https://www.questdiagnostics.com/home/ (January 31, 2020).
3.1.3 Dried blood spots microsample biobanking
Dried blood spots (DBSs) can be used for both real-time microsampling and subsequent ambient temperature biobanking for epidemiology and biomarker discovery (Figure 4). DBS samples can be particularly effective as a means of sample collection from participants in clinical trials. A survey by Tasso Inc. determined that a trial candidate may be more compliant to sample collection when given a less painful option for sample collection such as the OnDemand automated blood collection device for DBS collection and when done in the comfort of their own home (data unpublished) (Figure 5). Blood stabilized on the DBS can then be mailed by local postal services at the patient’s own convenience. Although storage of whole blood as DBS is an old technology, historically poor stability outside the lab environment, as well as low recovery levels and generally low quality of extracted nucleic acids and numerous blood proteins, has hindered its acceptance. In recent years, there has been development for a completely new, “smart health care,” paper-based sampling technology, which overcomes many of these known drawbacks. Deployed as a simple, painless skin prick onto a chemically treated collection card, the dried blood may then be recovered by ordinary magnetic bead or column-based DNA purification. With the resurgence of interest in the use of DBS for sample collection, research is being done to develop novel chemistries to yield RNA, DNA, and proteins with quality and quantity enough to support advanced analytical methods such as next generation sequencing and multiplex proteomics.
Figure 4.
Commercially available DBS collection devices for ambient storage and transportation. Biological samples collected remotely or stored at designated biobanks can utilize any one of the various products available for ambient storage of liquid samples. A number of formats of high-quality fiber-based media are available from Ahlstrom-Munksjö, Whatman-Qiagen, and others. The colorless format of cards is ideal for storage of colored biological samples such as fecal matter, plants, and whole blood. The colored cards are for storage of colorless biological samples such as serum, saliva, and other organics, at ambient. Biosample TFN card, AutoCollect card from Ahlstrom-Munksjö and Guthrie card, protein saver card from Whatman-Qiagen are ideal for collection of DBS needed for protein and small molecule analysis. The VAMS storage device from Neoteryx™ is convenient for patient-centric remote collection of microvolume samples. Some of the collection cards such as FTA, GenSaver, GenSaver Color cards and GenPlates are chemically treated for long-term preservation of DNA at ambient. These cards are ideal for biobanking and forensics application. AutoCollect card with perforated DBS circles are designed for automated sample preparation. GenPlates allow for high-throughput automated spotting of biological samples. The Tasso OnDemand collection device with integrated VAMS or paper cards is a painless alternative for volumetric collection of DBS. GenSaver, GenPlates, and GenReleaz cards allow for the convenience of direct downstream analysis (PCR, NGS, STR, etc.), from a 1-mm punch of DBS without any need for sample extraction. The 96-well format is ideal for storage of biobank samples and for screening and health monitoring applications. GenSaver 96 color, Indicating CloneSaver and GenPlates are designed for high-throughput biobanking needs.
Figure 5.
Patient survey for acceptance of blood collection method. Convenience, lack of pain, and simplicity of sample collection from donor will ensure compliance. As determined from a survey of 146 subjects, by Tasso Inc., on a pain scale of 1–10, the surveyed subjects graded the OnDemand device at 1.25, venipuncture at 2.25, and the lancet method of blood collection at >3.0. Of the 146 subjects, 83.4% preferred the least painful OnDemand method of blood collection compared to 15.9% by the lancet method (data courtesy of Tasso Inc.).
DBS is also associated with a 100-fold lower carbon footprint, being 100 times more compact (in terms of sample size) and it is readily suited for automated recovery from such solid-state blood specimens [42]. Long-term storage for multiple decades requires storage at −196°C under liquid nitrogen or on treated paper such as Whatman® FTA, Ahlstrom-Munksjö GenSaver™ cards. For short-term storage (weeks to a month), untreated paper such as Whatman 903 paper, Ahlstrom-Munksjö GenCollect™ paper, etc. may be used. The paper products work by drawing the water out of the sample causing localized dehydration of the sample. Specifically treated papers such as Whatman FTA and Ahlstrom-Munksjö GenSaver cards further stabilize the sample by either lysis of the cells and/or by prevention of various oxidative damage to the sample. Ribosomal RNA (18S and 28S rRNA) is more labile when stored in DBS, as demonstrated with a less than ideal RNA integrity number (RIN) below 6.5 (RIN values will be explained later on). Storage of blood on treated paper is superior to untreated paper for decades-long storage of DNA but to date there is no product available for storage of total RNA in whole blood for decades other than storing at −196°C.
Advances in non-invasive diagnostics for cancer where routine blood sample collection can be used for tracking progression of the disease is much more affordable and less painful than a solid tissue biopsy alternative. DBS microsample is a good alternative to collecting liquid whole blood in EDTA tubes by phlebotomy for individuals where tracking of progression of disease is crucial for prescribing treatment options. Advances in the quality and availability of highly sensitive instruments coupled with the development of software and methodological platforms for improved qualitative and quantitative analyses have made adoption of microsampling mainstream [43]. At home, blood collection of finger stick blood redundancy on microsampling devices such as GenSaver or FTA paper or on polymer compound, for example, Volumetric analytical MicroSampling (VAMS), is a convenient and a less painful alternative to phlebotomy. Advances in automation of almost pain-free microsampling of blood with the OnDemand by Tasso Inc. or Tap by Seventh Sense Biosystems are great alternatives for finger prick collection. Although opponents of precision medicine [34, 44] argue that matching the genotypic and phenotypic makeup of the individual to the treatment will not work, thus far, an individual-refined approach to selecting treatments has yielded demonstrable if still limited success.
3.1.4 Postmortem samples biobanking
Living donors contribute tissue samples only if it is a medical necessity. A possible viable source of large quantities of tissue samples is through postmortem collection of whole organs and tissues from consenting families. This avenue incurs a whole host of new challenges such as the donation consent process, recovery of organs and tissues in a limited time frame, postmortem, impact of donation on the donor families and steps necessary for creating a postmortem biobank such as IRB and registries. Carithers et al. [45] describe development of eligibility requirements aligned with scientific needs of the project and implementation of a successful infrastructure for biospecimen procurement to support the prospective collection, annotation, and distribution of blood, tissue, and cell lines and associated clinical data from postmortem samples. The development of donor eligibility criteria is crucial since limited donor history is available within the time frame needed for the collection of potential donor samples as degradation of biomolecules starts immediately with death. This proposition incurs a whole host of new challenges such as the donation consent process, recovery of organs and tissues in a limited time frame, postmortem, impact of donation on the donor families, and steps necessary for creating a postmortem biobank such as IRB and registries.
Sample collection is an intricate process that involves having many facets of the process coming together such as participant willingness, maintenance of anonymity of the sample source, and collecting samples in an ethically appropriate manner. Primarily, sample collection depends on the individual’s willingness to participate in the clinical study and their trust in the collecting institution. Higher participation rates may be anticipated if the need for the study results is focused on the greater good of the community [46]. Often the most problematic aspect of sample collection when collecting large number of donor samples is maintaining donor anonymity. The Kaiser foundation admits that donor personal information is vulnerable and has placed controls to mitigate the issue such as educating the donor as well as assigning an alternate identification to donor samples that are for the Precision Medicine Initiative [47].
Both private and federally funded institutions have set up repositories to collect and archive biological samples to be then made available to researchers globally through for-profit, paid services or for free through not-for-profit organizations. One such globally recognized institute, the Kaiser Foundation, launched their initiative in October of 2015 and has thus far accumulated over 220,000 samples through volunteers with an end goal of collecting a total of 500,000 samples [47, 48]. The Kaiser Foundation has the added advantage of possession of the patient’s lifestyle and EMRs that can be integrated along with the sample.
3.1.5 Nucleic acid extraction and storage
The quality and quantity of nucleic acid (DNA and RNA) depends on the quality of the nucleic acid in the starting material and the extraction method. There are many commercially available kits for extracting nucleic acids from varied sample types such as blood, PBMCs, serum, DBS, and fresh or frozen tissue samples. Decalcified FFPE samples are treated in the same manner as tissue samples. The common mechanism by which most nucleic acid extraction kits work is through lysis of the cells to release the nucleic acid followed by capture of the nucleic acid in chaotropic agents such as guanidinium salt on paramagnetic silica beads or on glass fiber filters. The silica beads or glass fiber filters are then washed to remove the proteins and cellular debris leaving relatively clean nucleic acid on the beads/filter. The nucleic acid is then released with a buffered elution solution most commonly Tris-EDTA at pH 8.3.
Extraction methods or kits must be chosen so they are well suited to the sample type [49, 50, 51, 52]. Nonetheless, there is varying opinion in the literature regarding the choice of nucleic acid extraction kit to use for different sample types. Molteni et al. [50] determined that the efficiency of extracting DNA from DBS on plain paper and Whatman FTA paper was better with Masterpure kit than with Qiagen’s QIAamp Blood mini kit and GenSolve DNA extraction kit (GenTegra LLC) being next best. In contrast, Daniels et al. of Broad Institute [52] determined that the efficiency of extracting DNA from DBS on Whatman FTA paper was superior with GenSolve DNA extraction kit than Qiagen’s QIAamp Blood mini kit. McClure et al. [53] report comparable quality of DNA extracted from DBS on Whatman FTA paper with the GenSolve DNA extraction kit to that extracted from whole blood samples. These DNA samples were compared on the Illumina BovineSNP50 iSelect BeadChip, which requires unbound, relatively intact (fragment sizes ≥2 kb), and high-quality DNA. Superior-quality total RNA can be extracted with the time-tested phenol extraction using the commercially available Tri Reagent, although good-quality total RNA can also be obtained by using commercially available RNA extraction kits (Zymo Research, Qiagen, and ThermoFisher). Agitation of the DBS sample in lysis solution at 40°C ensures more efficient extraction of RNA.
Clearly, the choice of method of nucleic acid extraction is dependent on prior sample expertise and analysis methods to be used for the study. A distinction between the quantity of nucleic acid extracted vs. the quality of nucleic acid is crucial, since having a large quantity of compromised nucleic acid will still result in an unsatisfactory outcome (Figure 6). A good check for the quality of DNA and RNA is by calculating the DNA Integrity Number (DIN) [54] or the RNA integrity number (RIN) [15, 55] of the sample by electrophoresis in the Agilent TapeStation or similar devices. Alternatively, the quality of DNA can also be assessed by amplification of a 3-kb to 7-kb fragment of a low copy housekeeping gene such as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) [56] and for RNA fragment >0.9 kb of a low copy gene such as RNase P [51].
Figure 6.
Quality and quantity of DNA from DBS. A volume of 125 μL of whole blood spotted on GenSaver, GenCollect, and Paper F (FTA) paper cards, these were stored for up to 10 years at ambient temperature (A). DNA extraction yields obtained from three 6-mm DBS punches of GenSaver and FTA paper cards, the amount of DNA obtained from the sample reduces with aging of the DBS. The quality of the DNA is influenced by the chemical protective agents added to the card (B). A 7.5-kb fragment of a single copy gene (GAPDH) was amplified from 5 ng of DNA from DBS on GenSaver, GenCollect, and FTA cards. DNA in DBS on GenSaver cards is 18× more stable than FTA and 4× more stable than GenCollect cards when a 7.5-kb fragment of a single copy gene (GAPDH) was amplified by polymerase chain reaction (PCR). A volume of 20 μL of the PCR product was subjected to electrophoresis on a 1.2% agarose gel (C). Gel electrophoresis of GAPDH 7.5-kb PCR product. Bands showing the PCR product from DBS in lanes 1–3 (GenCollect) and lanes 7–9 (FTA) are less intense than those of lanes 4–7 (GenSaver) for the 7.5-kb GAPDH product (D). Gel electrophoresis of GAPDH 3.8-kb PCR product. Product on lanes 1–3 comes from GenCollect DBS, product on lanes 4–6 comes from GenSaver DBS, products on lanes 7–9 comes from FTA DBS, lane 10 is the negative control and 11 is the positive amplification control, the intensities of the PCR product is not distinguishable among paper types. The differences in the intensities of the 7.5-kb and the 3.8-kb product indicate that the DNA is better protected from environmental effects in GenSaver cards. Samples were run on an E-gel.
Nucleic acid (both DNA and RNA) extracted from samples can be stored either at very low temperatures of −20, −80, or − 196°C or in a dry state by spray drying; lyophilization; air drying in the presence of commercially available protective chemistries such as RNAstable, DNAstable, (Biomatrica Inc., San Diego, CA), GenTegra-DNA [57] or GenTegra-RNA (GenTegra LLC, Pleasanton, CA); or by spotting on paper. The ribose-phosphate backbone in RNA molecules makes them susceptible to degradation. RNA consequently needs to be stored short term at −80°C or long term at ultra-low temperature of −196°C or in a precipitated form under ethanol. It is also possible to store RNA vitrified in the dry state at ambient temperature in the presence of protectants (GenTegra-RNA) that form the “glassy state” to prevent oxidative, hydrolytic, or RNase damage to the ribonucleic acid. The protective chemistries also allow the dry nucleic acid to re-dissolve easily because the chemistries prevent the formation of the gel-state that pure nucleic acids often form at high concentration. The gel-state makes solubilization very difficult without using mechanical forces that will also break the nucleic acid strands.
Oxygen and water are essential components in the generation of reactive molecules with the degradation process accelerating with increased temperature, reduced ionic strength of storage solution, increased concentration of divalent cations (greater than 5 ppb) or nucleolytic enzymes. In aqueous solutions (a convenient format for storage), nucleic acids are sensitive to depurination, depyrimidination, deamination, and hydrolytic cleavage. To inhibit this acid-catalyzed degradation of DNA, sample storage solutions for DNA need to be slightly alkaline buffered solutions such as tri-buffered to pH of 8.3. Nucleic acid extracted from clinical samples likely contain up to 30–40 ppb of iron (from heme or haem). Presence of even trace amounts of divalent cations (greater than 5 ppb) increases the oxidative degradation of nucleic acid due to the formation of highly reactive free radicals via Fenton reaction [58]. Adding chelating agents such as EDTA and EGTA to a concentration of 500 mM to the nucleic acid storage solution would ensure that the intrinsic divalent cations present in the clinical samples are chelated.
Dry storage of nucleic acids in the presence of protective chemistries causes the molecules to lose the ability to diffuse as the sample undergoes a non-crystalline amorphous phase or a “glassy state.” In this dry “glassy state,” the movement of protons is expected to be approximately one atomic diameter in 200 years, thus preventing both oxidative and nucleolytic degradation of the nucleic acid. Storage at ultra-low temperatures of −196°C also vitrified as the water becomes solid ice and the molecules lose their ability to move. If moisture is added to the dry sample or the temperature is raised in ultra-cooled samples above the glass transition temperature of water, DNA/RNA damage can occur as the proton movement and reactivity resume [59]. Trace amounts of RNase would also become active upon rehydration causing RNA damage.
Successful storage of biomolecules including nucleic acid is ultimately dictated by the purity of the extracted material. Highly pure total RNA samples from HeLa cells with a RIN of 10 can be stored dry for up to 6 years and 2 months at room temperature in GenTegra-RNA (Table 2) without appreciable loss of RNA integrity or strand breakage, but rat liver RNA that carries along cellular impurities in the extracted total RNA shows degradation of up to 0.2 strand breaks per kilobase, deterioration in RIN from 9.0 to 4.0 and a short storage life of 1 year and 8 months. Human blood lymphocyte RNA, like rat liver RNA (at an intermediate level of residual purity), displays more damage after 4 years as assessed by RIN analysis, suggestive of 0.4–0.5 RNA breaks per kilobase after 4 years of ambient temperature dry-state storage in GenTegra-RNA. WBC RNA, like rat liver RNA samples stored with additional 1 mm of EDTA, incurred much less damage upon 7 months of storage at 56°C (only about 0.1break/kb) (data not shown). RNA strand breakage (X) is determined from the calculated RIN value of the aged RNA to the RIN value of the unaged RNA stored at −20°C [60].
Table 2.
HeLa RNA, WBC RNA, and rat liver RNA in water, citrate, or EDTA buffer were stored in GenTegra-RNA for 4 years at ambient temperature (25°C). All of the samples were hydrated with water at the end of 4 years. RIN scores were analyzed by Bioanalyzer and average strand breaks calculated per kilobase (as determined by the negative natural log of ratio of peak heights of 28S-18S) at time equals 4 months to time zero (Rn) for the sample groups. The source of RNA and degree of RNase carryover was the key factor in determining the maintenance of a stable RIN score and development of number of strand breaks per kb and is independent of the type of buffer used for storage of the RNA.
4. Conclusion
Located in hospitals, universities, non-profit organizations, and pharmaceutical companies, biobanks are key infrastructures for research and development; however, these vaults for biospecimen are expensive to maintain and are precious samples that are not willingly shared. Nonetheless, biobanking provides invaluable insight into biomedical mysteries. The long-term translational studies allowed by maintaining archives of samples could provide valuable insight for future generations to treat chronic diseases. Currently, the research community hopes to use biobanking to push forward precision medicine, an initiative set forth by the Obama administration to form unique, targeted treatments for each individual [3, 6]. There is a two-fold challenge for sample collection, ensuring privacy and getting volunteers. Transparency and traceability of samples are key to governance of all human biospecimens. Living donors contribute tissue samples only if it does not directly affect the quality of their life. The development of donor eligibility criteria is crucial since limited donor history is available within the time frame needed for the collection of potential donor samples as degradation of biomolecules starts immediately with death. Thus, it is incredibly important to minimize the amount of time samples spend out of storage, in biobanks.
Biobanking biospecimens is an expensive endeavor both in terms of manpower and natural resources used. For example, a single −80°C freezer consumes as much energy as a small studio apartment. Most biobanks install a bank of −80°C freezers to store the biospecimen samples as each sample needs to be stored for 10 years as per CLIA and CAP guidelines. Many institutions store samples for longer than a decade for research, test development, and validation purposes. FFPE blocks are cataloged at ambient temperature room temperature making them the most efficient way of storing biospecimen samples. Most other sample types are presently stored in −80°C freezers for short-term storage or −196°C under liquid nitrogen for longer term storage. Although not yet mainstream, advances in microsampling analytical technologies has popularized ambient temperature biobanking of whole blood, whole blood components, fecal, urine, plasma, and serum biospecimens on paper such as treated GenSaver or FTA papers or on VAMS tips or Matrix chaperone. Nucleic acid can be stored at ambient temperature in the presence of protective stabilizers in a dry state with a choice of commercially available time-tested products such as GenTegra-DNA, GenTegra-RNA, DNAstable, RNAstable, RNAlater, etc. Ambient temperature storage is the most economical, environmentally friendly, low-carbon footprint, and practical way of storage when long-term storage for decades is needed. In addition to reducing molecular mobility, drying the samples removes water that can participate in hydrolytic reactions. Furthermore, storing samples in a dry state at ambient temperature is independent of environmental factors such as electrical supply, temperature, and humidity.
The Precision Medicine Initiative aimed at precisely and rapidly analyzing many more cancer genomes will bring about a deeper understanding of cancers fueled by discoveries of molecular diagnostic methods. The first fruits of precision medicine are already apparent as a wide range of nucleic acid and antibody/protein-based drugs have been optimized for individuals with favorable genetic makeup. With a goal of collecting a million samples for the Precision Medicine Initiative, storing the samples such as blood at −80 or −196°C for prolonged period (decades) is going to become impractical at some time. Consideration needs to be given to space and energy requirements for such an undertaking. A more practical approach is to consider dry ambient temperature storage of biomolecules that have a commercially available solution for storage. Although dry storage of nucleic acid and DBS at ambient temperature is an economical alternative, adoption of this concept by the research community would be a paradigm shift from the time-tested method of preservation by cryogenics. This could be due simply to availability of freezers for storing other sample types that yet do not have an ambient temperature storage method. A new technology introduced to the marketplace has a 30-year adoption cycle and dry storage is a couple decades into that cycle with increasing number of research facilities converting to ambient temperature storage where applicable. Biobanking of human samples has many ramifications that go beyond the science and technology of their storage. There are national, state, and even local regulations that must be met to ensure the protection of individual rights and individual privacy. Educating donors on the purpose of biospecimen collection and assurance of maintaining the privacy of the donor has favorable outcome. Perhaps it is reasonable to consider in a future review these legal and privacy issues.
\n',keywords:"biobanking, precision medicine, dried blood spots (DBS), nucleic acid, ambient temperature storage, translational studies",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71889.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71889.xml",downloadPdfUrl:"/chapter/pdf-download/71889",previewPdfUrl:"/chapter/pdf-preview/71889",totalDownloads:186,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"September 3rd 2019",dateReviewed:"March 4th 2020",datePrePublished:null,datePublished:"June 24th 2020",dateFinished:null,readingETA:"0",abstract:"Biobanking increases the rate at which precision medicine can be used to successfully refine currently existing medical treatment methodologies. The purpose of precision medicine is to increase a patient’s likelihood of defeating a chronic disease, by creating a unique and personal treatment method. However, the research necessary to develop precision medicine requires thousands of biospecimens, which is why biobanking is necessary to move precision medicine forward. Traditional biobanks are a library of preserved biological specimens, such as tissue and whole blood, that can be later accessed for further testing and analysis. Maintaining these types of biobanks is cumbersome and expensive, due to freezer care. Biobank samples are used to support therapeutic drug monitoring in clinical trials, epidemiology, public health screening, and biomarker discovery. Collecting samples for large translational studies requires making regular trips to the phlebotomist or a clinic, which is an inconvenience that is exacerbated when collecting samples in remote and/or resource-limited locations. Inconsistencies in sample collection can affect downstream clinical studies. Remedies for these procedural issues include the development of a medium that effectively preserves the samples at ambient temperature and developing a virtual biobanking system that allows for long-distance access to bioinformatic data of previously analyzed biospecimens.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71889",risUrl:"/chapter/ris/71889",book:{slug:"biochemical-analysis-tools-methods-for-bio-molecules-studies"},signatures:"Armaity Nasarabadi Fouts, Alejandro Romero, James Nelson, Mike Hogan and Shanavaz Nasarabadi",authors:[{id:"311399",title:"M.Sc.",name:"Shanavaz",middleName:null,surname:"Nasarabadi",fullName:"Shanavaz Nasarabadi",slug:"shanavaz-nasarabadi",email:"shanavazn@gentegra.com",position:null,institution:null},{id:"312331",title:"Dr.",name:"Michael",middleName:null,surname:"Hogan",fullName:"Michael Hogan",slug:"michael-hogan",email:"mikehogan12752@earthlink.net",position:null,institution:null},{id:"316859",title:"Mrs.",name:"Armaity",middleName:null,surname:"Fouts",fullName:"Armaity Fouts",slug:"armaity-fouts",email:"armaitynasarabadi032@gmail.com",position:null,institution:null},{id:"316860",title:"Mr.",name:"Alejandro",middleName:null,surname:"Romero",fullName:"Alejandro Romero",slug:"alejandro-romero",email:"alejandror@gentegra.com",position:null,institution:null},{id:"316873",title:"Dr.",name:"James",middleName:null,surname:"Nelson",fullName:"James Nelson",slug:"james-nelson",email:"jamesn@gentegra.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Precision medicine",level:"1"},{id:"sec_3",title:"3. Biobanking",level:"1"},{id:"sec_3_2",title:"3.1 Sample types used for biobanking",level:"2"},{id:"sec_3_3",title:"3.1.1 Tissue",level:"3"},{id:"sec_4_3",title:"Table 1.",level:"3"},{id:"sec_5_3",title:"3.1.3 Dried blood spots microsample biobanking",level:"3"},{id:"sec_6_3",title:"3.1.4 Postmortem samples biobanking",level:"3"},{id:"sec_7_3",title:"Table 2.",level:"3"},{id:"sec_10",title:"4. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Alers JC, Krijtenburg P-J, Vissers KJ, van Dekken H. Effect of bone decalcification procedures on DNA In situ hybridization and comparative genomic hybridization: EDTA is highly preferable to a routinely used acid decalcifier. The Journal of Histochemistry and Cytochemistry. 1999;47:703-709'},{id:"B2",body:'Alegría-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics. 2011;3:267-277'},{id:"B3",body:'Jaffe S. 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Patient views on the use of personal health information and biological samples for biobank research. Journal of Patient-Centered Research and Reviews. 2017;4:171'},{id:"B47",body:'Kaiser Permanente Expands Precision Medicine Biobanking Effort. Available from: https://healthitanalytics.com/news/kaiser-permanente-expands-precision-medicine-biobanking-effort'},{id:"B48",body:'Permanente, K. Kaiser Permanente Research Bank Consent Form. Available from: https://researchbank-econsent.kaiserpermanente.org/(X(1)S(p1ehme24jg1janrg12rgdzfm))/ConsentForm/ConsentForLocalPrint/?AspxAutoDetectCookieSupport=1'},{id:"B49",body:'Choi EH, Lee SK, Ihm C, Sohn YH. Rapid DNA extraction from dried blood spots on filter paper: Potential applications in biobanking. Osong Public Health and Research Perspectives. 2014;5:351-357'},{id:"B50",body:'Molteni CG et al. Comparison of manual methods of extracting genomic DNA from dried blood spots collected on different cards: Implications for clinical practice. International Journal of Immunopathology and Pharmacology. 2013;26:779-783'},{id:"B51",body:'Olsvik PA, Lie KK, Jordal AEO, Nilsen TO, Hordvik I. Evaluation of potential reference genes in real-time RT-PCR studies of Atlantic salmon. BMC Molecular Biology. 2005;6'},{id:"B52",body:'Daniels R, Volkman SK, Milner DA, Mahesh N, Neafsey DE, Park DJ, et al. A general SNP-based molecular barcode for Plasmodium falciparum identification and tracking. Malaria Journal. 2008;7:223. DOI: 10.1186/1475-2875-7-223'},{id:"B53",body:'McClure MC, McKay SD, Schnabel RD, Taylor JF. Assessment of DNA extracted from FTA® cards for use on the Illumina iSelect BeadChip. BMC Research Notes. 2009;2:107'},{id:"B54",body:'Padmanaban A. DNA Integrity Number (DIN) For the Assessment of Genomic DNA Samples in Real-Time Quantitative PCR (qPCR) Experiments Application Note Author'},{id:"B55",body:'Mueller O, Lightfoot S, Schroeder A. RNA Integrity Number (RIN)-Standardization of RNA Quality Control Application'},{id:"B56",body:'Kozera B, Rapacz M. Reference genes in real-time PCR. Journal of Applied Genetics. 2013;54:391-406'},{id:"B57",body:'McDevitt SL, Hogan ME, Pappas DJ, Wong LY, Noble JA. DNA storage under high temperature conditions does not affect performance in human leukocyte antigen genotyping via next-generation sequencing (DNA integrity maintained in extreme conditions). Biopreservation and Biobanking. 2014;12:402-408'},{id:"B58",body:'Graf E, Mahoneys JR, Bryant RG, Eaton JW. Iron-catalyzed hydroxyl radical formation. The Journal of Biological Chemistry. 1984;259:3620-3624'},{id:"B59",body:'Williams RJ, Leopold AC. The glassy state in corn embryos. Plant Physiology. 1989;89:977-981'},{id:"B60",body:'Nasarabadi S, Hogan M, Nelson J. Biobanking in precision medicine. Current Pharmacology Reports. 2018;4:91-101'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Armaity Nasarabadi Fouts",address:null,affiliation:'
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1. Introduction
Malignant migrating partial seizures of infancy (MMPSI) is a rare and usually an unrecognized epileptic syndrome of infancy. The International League Against Epilepsy defines this form of epilepsy as follows: seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, combined with multifocal ictal EEG discharges, and progressive deterioration of psychomotor development [1, 2, 3]. Exact criteria of MMPSI are not defined and are being developed. According to the draft of the Classification of the Epilepsies 2001, this syndrome refers to presumably symptomatic neocortical focal epilepsy. In the new Classification of the Epilepsies 2017 (ILAE 2017), MMPSI has not found a separate place, but it is implied that it includes in a group of developmental and epileptic encephalopathy.
This severe form of epilepsy was recently described. The first publication about migrating partial seizures of infancy was presented by Coppola and colleagues in 1995 [1], and then personal observations were done by Gerard et al. [4] and by Okuda et al. [5]. Veneselli et al. summarized previous observations and added three own cases [6]. Coppola et al. in their remarkable report (1995) based on neuropediatric department at the René Descartes University (Paris) presented 14 clinical cases of infants of both sexes with previously undescribed epileptic syndrome characterized by virtually continuous multifocal seizures. According to the classical authors description, the first seizures occurred average at the age of 3 months without any significant previous events. During the period from 1 to 10 months, seizures became very frequent. Seizures were focal and had different clinical characteristics; EEG revealed multiple epileptiform discharges arising independently and with migration during subsequent seizures from one cortical region to another. Patients had regression of psychomotor development, tetraparesis and severe muscular hypotonia of axial muscles. Three of 14 patients died: one at the age of 7 months, and other at the age of 7 and 8 years. Seizures were completely ceased only in two patients. In most cases the cause of the disease was not identified; and there were no family cases [1].
In 2005, Dulac summarized 24 patients’ follow-up (the largest number of verified cases in the world) in the Saint Vincent de Paul Hospital in Paris. Marsh et al. [25] reported another six cases of MMPSI observed in the Philadelphia Children’s Hospital University of Pennsylvania who met the criteria described by Coppola. Presented clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy for the whole world epileptology [3].
Synonyms of this epileptic syndrome in the world scientific literature are malignant migrating partial seizures of infancy, migrating partial seizures of infancy, malignant epilepsy of infancy with migrating multifocal seizures, Coppola-Dulac syndrome, and most genetic verified cases, which can be referred to early infantile epileptic encephalopathy type 14 (EIEE14).
2. Etiology
In most MMPSI cases, etiology remains unknown; familial cases are rare. In observation by Dulac, relatives in 3 of 24 patients had febrile convulsions, and 4 patients had family history of epilepsy [3]. Multiple tests for inherited metabolism defects had negative results [7].
2.1 Monogenic mutations with Mendelian type of inheritance
The first genetic sequencing for identification mutations specific for MMPSI was carried out by Coppola et al. [8]. Was performed automatic sequencing of genes of potassium (KCNQ2, KCNQ3) and sodium (SCN1A, SCN2A) ion channels in three children with MMPSI but no mutation have been found. Mutational screening of chloride (CLCN2) ion channel gene revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. But the same variation has been found in 38 out of 100 control alleles [8].
At present time a number of monogenic mutations were identified in patients with malignant migrating partial seizures of infancy. In catalog of human genes and genetic disorders – Online Mendelian Inheritance in Man (OMIM), we could find the following positions for MMPSI phenotype (Table 1):
Phenotype OMIM classification
Phenotype OMIM number
Gene/locus
Gene OMIM number
Location
Mutation variants
Inheritance
References
Early infantile epileptic encephalopathy type 3 (EIEE3)
Monogenic mutations as etiological factors of malignant migrating partial seizures of infancy
2.1.1 Early infantile epileptic encephalopathy type 3 (EIEE6; 609304)
Poduri et al. [9] reported about two sibs (brother and sister), born of consanguineous Saudi Arabian parents, with EIEE3 presenting MMPSI phenotype. EEG showed abnormal spikes in various brain regions. Neurological signs included hypotonia and brisk tendon reflexes; psychomotor development was delayed and subsequently arrested. Brain MRI was normal in the boy but showed delayed myelination and diffuse thinning of the corpus callosum in his sister. Two sibs had polymorphic seizures including bilateral and hemiclonic convulsions, flushing of the face, “staring,” and eventually bilateral eyelid blinking. The seizures in both children were refractory to treatment. The boy developed seizure onset at 1 week of age and died at 14 months; the girl presented first seizures at 2 weeks of age and died at 47 months of age. They also had two healthy brothers. The research team analyzed consanguineous pedigree (parents are cousins) and obtained DNA from affected and unaffected family members, analyzed single nucleotide polymorphism (SNP) 500 K data to identify regions with evidence for linkage, performed whole-exome sequencing, analyzed homozygous variants in regions of linkage to identify a candidate gene, and performed functional studies of the candidate gene SLC25A22. In affected siblings, a homozygous c.328G-C transversion in the SLC25A22 gene was identified, resulting in a gly110-to-arg (G110R; 609302.0003) substitution at a highly conserved residue in the third transmembrane helix [9].
2.1.2 Early infantile epileptic encephalopathy type 6 (EIEE6; 607208)
It is a well-known fact that mutation in SCN1A is a leading etiological factor for severe myoclonic epilepsy of infancy (Dravet syndrome). OMIM genetic classification is early infantile epileptic encephalopathy type 6 (607208) with autosomal dominant inheritance. Nevertheless, Freilich et al. [10] have found a novel mutation in the SCN1A gene in the girl with MMPSI who died at the age of 9 months from recurrent status epilepticus (SE). This girl had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, SE of migrating multifocal seizures confirmed by EEG monitoring, progressive microcephaly, and profound psychomotor delay. By sequencing genomic DNA from blood, the heterozygous missense mutation c.C5006C > A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E; 182389.0023), which further was confirmed in brain DNA, was identified. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein [10].
In a scientific group of Epilepsy Research Centre, Department of Medicine, University of Melbourne, Australia, Carranza Rojo et al. [11] have investigated 15 unrelated children with MMPSI for mutations in genes associated with infantile epileptic encephalopathies (SCN1A, CDKL5, STXBP1, PCDH19, and POLG). One girl with seizure onset at 2 weeks had heterozygous missense mutation de novo 2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G; 182389.0024) that affects the sodium channel by substitution in the voltage sensor segment S4 of the second protein domain. She had epilepsy onset of alternative hemiclonic seizures (Dravet-like onset) at the age of 2 weeks with developing status epilepticus of multifocal migrating seizure. Also, the girl had acquired microcephaly, developmental regression, and severe intellectual disability with much more severe phenotype than children with Dravet syndrome. And, another girl who developed MMPSI at the age of 2 months had de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screenings of CDKL5, STXBP1, and PCDH19 and the three common European mutations of POLG were negative [11].
Along with Dravet and MMPSI syndromes, mutation in SCN1A gene has been also associated with generalized epilepsy with febrile seizures plus type 2 (604403), familial febrile seizures type 3A (604403), and familial hemiplegic migraine type 3 (609634). All the diseases have autosomal dominant inheritance.
2.1.3 Early infantile epileptic encephalopathy type 13 (EIEE13; 614558)
Ohba et al. [12] identified in seven unrelated patients with early-onset epileptic encephalopathies seven different de novo heterozygous missense mutations in the SCN8A gene, and one of them had MMPSI. In a 5-year-old bedridden severe delayed and profound intellectual disabled Japanese boy by whole-exome sequencing, de novo previously not described mutation in SCN8A gene c.2537 T > C (p.Phe846Ser) was detected. He developed apnea seizures from the age of 2 months and further at 4 months demonstrated migrating hemiclonic convulsions increasing up to status epilepticus of multifocal migrating seizures. MRI has shown mild atrophy of the cerebellum and thin corpus callosum. High-dose combined antiepileptic therapy with phenobarbital, phenytoin, and lamotrigine, ketogenic diet, and vagus nerve stimulator (VNS) implantation are temporarily and partially effective [12].
Voltage-dependent sodium channels, such as SCN8A, are responsible for the initial membrane depolarization that occurs during generation of action potentials in most electrically excitable cells. Mutations in KCNT1 aside from EIEE13 also determine benign familial infantile seizures type 5 (OMIM 617080) and cognitive impairment with or without cerebellar ataxia (OMIM 614306) with autosomal dominant inheritance.
2.1.4 Early infantile epileptic encephalopathy type 14 (EIEE14; 614959)
Barcia et al. in 2012 had identified four different de novo heterozygous mutations in the KCNT1 gene (608167.0001–608167.0004) in 6 of 12 unrelated pediatric patients (50%) with clinically manifestation as MMPSI. The gene KCNT1 encodes a sodium-activated potassium channel that is widely expressed at the nervous system. Its activity contributes to the slow hyperpolarization as the neuronal membrane potential that follows repetitive firing. The C-terminal cytoplasmic domain interacts with a protein network, including FMRP (fragile X mental retardation protein), suggesting additional functions [13].
OMIM genetic classification for this type of MMPSI is early infantile epileptic encephalopathy type 14 (614959). At present time, the following allelic variants of KCNT1 gene mutation in patients with MMPSI were identified:
ARG428GLN (608167.0001 KCNT1). It was founded by Barcia et al. [13] in three unrelated patients of French origin and was identified as de novo heterozygous 1283G-A transition in exon 13 of the KCNT1 gene, resulting in an arg428-to-gln substitution at a highly conserved residue in the cytoplasmic C-terminal domain.
ALA934THR (608167.0002 KCNT1). In a child of French origin with MMPSI, Barcia et al. [13] identified a de novo heterozygous 2800G-A transition in exon 24 of the KCNT1 gene, resulting in an ala934-to-thr substitution at a highly conserved residue in the cytoplasmic C-terminal domain. The mutation was shown to cause constitutive activation of the sodium-activated potassium channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C activation.
ARG474HIS (608167.0003 KCNT1). It was identified in a patient of French origin with MMPSI by Barcia et al. [13] as de novo heterozygous 1421G-A transition in exon 15 of the KCNT1 gene, resulting in an arg474-to-his substitution at a highly conserved residue.
ILE760MET (608167.0004 KCNT1). It was also founded by Barcia et al. [13] in a child of Ukrainian origin with early clinical manifestation of MMPSI and was identified as de novo heterozygous 2280C-G transversion in exon 20 of the KCNT1 gene, resulting in an ile760-to-met substitution at a highly conserved residue.
All these mutations were identified by exome sequencing and also were confirmed by Sanger sequencing. Mutations were not found in 200 controls or in several large control databases [13].
PHE932ILE (608167.0009 KCNT1). Vanderver et al. [14] identified in an Australian boy the de novo heterozygous c.2794 T-A transversion in the KCNT1 gene, resulting in a phe932-to-ile substitution at a highly conserved residue in the cytoplasmic C-terminal domain. This mutation was found by whole-exome sequencing, confirmed by Sanger sequencing, and was not present in the 1000 Genomes Project or Exome Sequencing Project databases. Seizure onset was at age of 1 month with refractory myoclonic seizures that progressed to different polymorphic seizure types and status epilepticus. He also had microcephaly and severe developmental stagnation. Brain imaging showed serious delayed myelination, and EEG demonstrated background slowing with multifocal interictal discharges and occasional periods of burst suppression. The patient doesn’t have classical MMPSI characteristics and survived (last observation at the age of 10) with a decrease of pharmacoresistant seizures at the age of 7 [14].
GLY288SER (608167.0010 KCNT1). Ishii et al. in two unrelated Japanese girls with MMPSI identified a de novo heterozygous c.862G-A transition in the KCNT1 gene, resulting in a gly288-to-ser substitution at a highly conserved residue in the pore region of the channel [15].
Kawasaki et al. described three infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral arteries with life-threatening hemoptysis and heart failure [16].
Madaan with colleagues from Child Neurology Division, Department of Pediatrics, All India Institutes of Medical Sciences (New Delhi, India), in 2018 identified a child with MMPSI who had a novel heterozygous missense mutation in exon 10 of the KCNT1 gene (chr9:138650308; c.808C > C/G (p.Q270E)). Neither quinidine nor ketogenic diet could control his seizures, and the child succumbed to his illness at 9 months of age [17].
My personal observation consists of two Russian girls with MMPSI having KCNT1 mutations: one with gly288ser (608167.0010 KCNT1) and the other with previously not described mutations c.1066C > T (arg356trp) in exome 12 (chr9:138656907C > T, rs752514808). So, it seems that KCNT1 is a major disease-associated gene for the MMPSI phenotype.
It is interesting that mutations in KCNT1 also determine another form of epilepsy – nocturnal frontal lobe epilepsy type 5. But the mutation is different from the cases of MMPSI and is marked .0005–.0008 (ARG928CYS, TYR796HIS, ARG398GLN, and MET896ILE).
2.1.5 Early infantile epileptic encephalopathy type 16 (EIEE14; 615338)
Milh et al. [18] identified compound heterozygosity for two mutations in exon 2 of the TBC1D24 gene (686 T-C transition, resulting in a phe229-to-ser, 613577.0005, and 468C-A transversion, resulting in a cys156-to-ter, 613577.0006) in two sisters with malignant migrating partial seizures of infancy. These girls early developed clonic seizures in the second month of life and subsequently demonstrated prolonged, almost continuous migrating seizures of different types with severe neurologic deterioration and lack of psychomotor development [18].
OMIM genetic classification for this type of MMPSI – early infantile epileptic encephalopathy type 16 (615338). The screening of TBC1D24 in an additional set of eight MMPSI patients observed by Milh and colleagues was negative. The TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins, which coordinates peripheral membrane Rab proteins and other GTPases for the proper transport of intracellular vesicles. Coimmunoprecipitation studies showed that the phe229ser mutation impaired the interaction of TBC1D24 with adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6, 600,464), and overexpression of the mutant protein in primary cortical neurons abolished the ability of TBC1D24 to increase neurite length and arborization, consistent with a loss of function [18].
Mutation in TBC1D24 gene has been also associated to infantile familial myoclonic epilepsy (OMIM 605021, autosomal recessive inheritance), DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndrome – OMIM 220500) with autosomal recessive inheritance, and also autosomal recessive deafness type 86 (614617), and autosomal dominant deafness type 65 (616044).
2.1.6 Progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA; 615760)
Zhang et al. [19] in four patients from two unrelated families with progressive microcephaly, intractable seizures, and cerebral and cerebellar atrophy (MSCCA; 615,760) identified compound heterozygous mutations in the QARS gene (603727.0001–603727.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. QARS (or GLnRS; 603,727) is a class I aminoacyl-tRNA synthetase. Aminoacyl-tRNA synthetases are enzymes that charge tRNAs with their cognate amino acids. The specificity of this reaction determines the fidelity of mRNA translation. At least one synthetase exists in the cytoplasm for each amino acid. QARS is essential for normal brain development. Studies in patient cells and expression of recombinant variants in E. coli showed that all four mutations caused a severe loss of QARS catalytic activity, consistent with a loss-of-function effect. Homozygous loss of QARS in zebrafish caused decreased brain and eye size and extensive cell death in the brain. Two sibs observed by Zhang et al. [19], born of unrelated French parents, had clinical and EEG signs of malignant migrating partial seizures of infancy and compound heterozygous mutations in the QARS gene, a c.169 T-C transition, resulting in a tyr57-to-his (603727.0003) substitution at a highly conserved residue in the N-terminal domain, and a c.1543C-T transition, resulting in an arg515-to-trp (603727.0004) substitution at a highly conserved residue in the catalytic domain. Patient cells showed decreased aminoacylation activity of QARS compared to control. Expression of recombinant arg515trp (.0004) in E. coli resulted in no QARS catalytic activity, whereas tyr57his (.0003) decreased QARS activity to less than 10% that of controls. In addition, the arg515trp mutation appeared to cause protein misfolding and aggregation, resulting in decreased expression of the soluble mutant protein [19].
2.1.7 Rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222765)
On personal observation of MMPSI patients, one Russian boy with clinical and electroencephalographic pattern of mixed form (MMPSI and early myoclonic encephalopathy) had rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222,765) from the group of peroxisomal metabolic diseases [20]. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) is caused by homozygous or compound heterozygous mutation in the DHAPAT gene (GNPAT; 602,744), which encodes acyl-CoA:dihydroxyacetonephosphate acyltransferase, on chromosome 1q42. This peroxisomal disorder is characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, micrognathia, dysplastic external ears, eye abnormalities‑cataract and coloboma, congenital contractures, dwarfism, hypotonia, and severe mental retardation. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective.
2.2 Chromosome aberrations
At 2010 group of genetics from the Department of Pediatrics, University of Michigan (Ann Arbor, Michigan, USA), has found de novo 598 kb 16p11.2 microduplication in a boy with refractory MMPSI, who has developed seizures in 4 months and also has spastic quadriparesis, severe global developmental delay, hypotonia, and microcephaly [21].
In 2012 Poduri and colleagues from the Department of Neurology of Children’s Hospital Boston (Massachusetts, USA) in a patient, born of consanguineous Palestinian parents, with clinical manifestation as MMPSI, identified a homozygous 486-kb deletion on chromosome 20p12.3 encompassing the promoter region and exons 1, 2, and 3 of the PLCB1 gene. The deletion breakpoints were mapped from 8,094,049–8,094,072 to 8,580,261–8,580,284 (GRCh37). The breakpoints lie within two LINE nuclear elements and likely arose from nonallelic homologous recombination. PLCB1 gene (607,120; locus 20p12.3) is responsible for early infantile epileptic encephalopathy type 12 (EIEE12; 613,722). Phospholipase C-beta (PLCB) catalyzes the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (IP2), a key step in the intracellular transduction of many extracellular signals. The PLCB1 gene encodes a mammalian PLCB isoform that is expressed in cerebral cortex, hippocampus, amygdala, lateral septum, and olfactory bulb [22].
2.3 Other etiological factors
Most cases of MMPSI are considered as unknown etiology (cryptogenic). But also MMPSI had its symptomatic analogs including cases considered as dual pathology [1, 2, 3, 20, 23].
In two of three cases for the first time presented by Coppola et al., neuropathologic brain examination showed marked loss of hippocampal neurons in combination with gliosis in the CA1 sector of hippocampal pyramidal layer [1, 23].
Personal observation of 35 cases with MMPSI contains 12 children with symptomatic clinical-electroencephalographic copies of MMPSI (5 boys and 7 girls). Only two infants had cerebral dysgenesis: lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Other ten children had severe perinatal hypoxic-ischemic CNS disturbances (four of them mixed with perinatal infections‑cytomegalovirus, ureaplasma, chlamydia, herpes type 1) that caused serious brain damage, tetraparetic spastic form of cerebral palsy, and severe retardation in combination with epileptic encephalopathy. Their clinical and video-EEG signs demonstrated MMPSI picture.
3. Clinical signs
At the present time, at least about 100 cases of MMPSI appear to be described in the world literature. However, the number of publications has been steadily growing in recent years. Obviously, this serious disease is more common than diagnosed due to the low clinicians’ awareness. In the structure of patients with onset of status epilepticus before 3 years of age (n = 267), a group of children with MMPSI consisted 4.9% (n = 13), and in the structure of infant with SE (n = 147) – 8.8% [24].
Both sexes are equally susceptible. According to Dulac, 20 children with MMPSI included 9 girls and 11 boys [3]. Disease onset varies in age from 1 week to 7 months of life (average – 3 months) [1, 4]. According to Marsh et al., seizures onset varied from the first days to 3 months (average – 25 days) [25].
In most cases, pattern of the first seizure includes motor component of one limb or half of the body; and 50% of the patients develop secondary generalization. In some cases after seizure onset, their frequency uncontrolled rapidly rises to status epilepticus. However, seizures could have longer duration, but at onset seizures often go unrecognized. Cases with autonomic manifestation (episodes of apnea, short blackouts with cyanosis or redness) are difficult to diagnose [3]. Thus, in observation by Gerard et al. [4], epileptic seizures with diffuse erythema and sweating with subsequent hiccups were reported as gastroesophageal reflux, and only a few weeks later, addition of focal seizures was noted, which made diagnosis obvious [4]. According to observations by Dulac, the initial period of the disease usually lasts from 1 week to 3 months (average – 45 days). During this period, seizures may be quite rare, for example, once a week [3].
In the age of 24 days to 10 months (mean 4.5 months), seizures become very frequent and polymorphic but usually are still focal. Seizures usually get clustered (serial) nature, mental and motor retardation is clear. Clinical manifestation of seizures may include head and eye version, lateralized eyeball twitching, fixed gaze, clonic eyelid twitching, tonic tension or clonic spasms of one limb or hemispasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. One patient may have multiple different combinations of seizures. Typically, seizure duration is 1–4 minutes, but in some cases, it may persist up to several 1 of minutes, until the status epilepticus development. As far as the disease progresses, secondary generalized seizures became more frequent. Seizures are almost continuous or occur as a series 5–30 times per day, mainly on awakening and when falling asleep. Seizure periods may alternate with clear periods when seizures occur within 2–5 days continuously, and then there are several “light” days (the cyclic course of disease) [1, 2, 3, 26].
It should be considered that many seizures are hardly noticeable visually and often remain unrecognized for parents and medical staff. In particular, these are “volatile” paroxysms, as short episodes of apnea, episodes of eyes closing or eyes deviation, episodes of facial flushing, etc. Only video-EEG monitoring can prove the epileptic genesis of paroxysmal phenomena.
The course of the disease and the severity of clinical symptoms often have undulating pattern: a period of severe illness and permanent seizures may continue for several weeks, and then it is replaced by a relatively favorable period of the temporary seizure regression and some improvement in cognitive and motor functions. This phenomenon generates additional difficulties in controlling the quality of care as it is quite difficult to differentiate in which case the decrease in frequency and severity of seizures is a true response to therapy and in which case it is subject to the course of the disease.
Under personal observation of patients with MMPSI, age of seizure onset ranged from the 1st day of postnatal life up to 6 months of life. MMPSI were characterized by marked polymorphism (Table 2) and high frequency of epileptic seizures and were in fact a special form of infantile status epilepticus (SE) in the form of migrating multifocal SE. All patients had five or more types of epileptic seizures.
Seizure types
Patients (n)
%
Tonic versive seizures
35
100
Tonic spasms
33
94.3
Ophthalmo-tonic seizures
35
100
Ophthalmo-clonic seizures
11
31.4
Atonic seizures
23
65.7
Dialeptic (pseudoabsences)
19
54.3
Pharyngo-oral seizures
18
51.4
Tongue clonus
7
20
Hemiclonic
19
54.3
Jacksonian march
11
31.4
Automotor
8
22.9
Apnea with cyanosis
14
40
Autonomic with vomiting
5
14.3
Focal myoclonic
18
51.4
Bilateral myoclonic
13
37.1
Fragmentary “erratic” myoclonus
5
14.3
GTCS
14
40
SE of migratory minor motor seizures
35
100
SE of inhibitory seizures
12
34.3
Hemiconvulsive SE
11
31.4
SE of tonic spasms
10
28.6
Myoclonic SE
9
25.7
SE of GTCS
8
22.9
Table 2.
Epileptic seizure types in patients with malignant migrating partial seizures of infancy (n=35)
Neurological findings in MMPSI children marked with neurological impairment from birth‑severe central tetraparesis, often with muscular hypotonia in the axial and limb muscles [1], microcephaly, strabismus, and athetoid hyperkinesis [25]‑are common. Many patients in dynamics are unable to walk and sit without support and in severe cases are also unable to control the vertical head position, drink, and swallow. In all cases, there is mental retardation, usually severe, and visual agnosia [3].
Personal patients with MMPSI (n = 35) in neurological status had a high representation of various disorders: high level of stigmatization was observed in 15 patients (42.8%), 13 patients (37.1%) had microcephaly, and optic nerve atrophy was observed in 27 patients (77.1%). Disorders of bulbar innervation were observed in all patients, while in nine children (25.7%), these impairments were bulbar syndrome, and in 26 children (74.3%) – pseudobulbar syndrome. All patients with MMPSI had changes in the muscle tone: 10 children (28.6%) had spastic hypertonus, 16 children (45.7%) had diffuse muscle hypotonia, and 9 children had dystonic changes (25.7%). Severe movement disability with tetraparesis was formed in all of the children with MMPSI. Neurological disorders were expressed at birth (n = 16, 45.7%) or developed with the onset of seizures (n = 19, 54.3%) and tended to a steady progression in all the patients. All children with MMPSI had delay of motor and mental development (n = 35, 100%), up to a complete development stop in 26 infants (74.3%).
4. Electroencephalographic findings and neuroimaging
4.1 EEG and video-EEG monitoring
Diffuse slowing of the main background activity is typical that is revealed in the first EEG recordings. At first epileptic cause of these EEG phenomena may remain undetected, especially if symptoms include only short autonomic paroxysms. Epileptiform disorders in disease onset are rare. However, in 3 of 14 patients in the observation by Gerard et al. [4], originally normal background EEG was observed; later, slowing with variable asymmetry was recorded in all cases. Often, slow-wave accentuation in one of the EEG recordings is more pronounced in one hemisphere, while the later study may reveal dominating slow-wave lateralization from the opposite side. Multiregional spikes without clear activation during sleep are registered in all cases during development of the disease. However, pathognomonic interictal EEG pattern in MMPSI is absent. During the period relatively free of seizures, stage differentiation in the structure of sleep EEG may persist, but sleep spindles are rare and usually asymmetric [3]. When seizures become very frequent, interictal activity is almost absent.
Ictal EEG patterns involve different areas of the cerebral cortex in the course of successive seizures. Ictal pattern is a rhythmic activity of alpha and theta range, occurring in one region with adjacent regions involvement during seizure, followed by a gradual decrease of the frequency characteristics. Caraballo with colleagues, analyzing 17 infants with MMPSI, had distinguished three different EEG patterns: 8 cases with alternating simple focal motor seizures at onset, and the ictal EEG pattern was characterized by recurrence of rhythmic focal spikes or rhythmic sharp theta or alpha activity in the Rolandic region; 5 cases with complex focal seizures and progressive appearance of polymorphic theta-delta in temporo-occipital regions recurring independently; and 4 cases with focal complex seizures with motor manifestations and ictal EEG with flattening or fast activity in frontotemporal region followed by unilateral fast polyspikes in alternating clusters in both hemispheres. Correlations between these three patterns with severity or prognosis were not found [27]. Electro-clinical seizure patterns last from 1 to 4 minutes. Multiple subclinical ictal EEG patterns lasting from 30 seconds to 1 minute are also typical [1]. Observations show an alternative cortical section of both hemispheres’ involvement in epileptogenesis, which implies the presence of a diffuse pathological process in the cerebral cortex [3].
When seizures become very frequent, initial zone of ictal pattern shift from one region to another and from one hemisphere to another occurs. As a result, extended, migratory ictal activity, which forms a complex EEG pattern of status epilepticus, develops [1, 2, 3].
Video-EEG monitoring plays the most important role in the MMPSI diagnosis, as it is able to detect a correlation between ictal pattern localization of and clinical characteristics of seizure. Thus, ictal pattern in the frontal region produces clinical signs in the form of tonic tension or clonic spasms in the contralateral limb; ipsilateral automatisms or a versive seizure with alternating tonic phenomena and fencing posture are possible. EEG pattern is localized in perirolandic area and manifests with contralateral clonus of the lips, tongue, facial muscles, and hypersalivation. Temporal EEG patterns clinically manifest with broad “frozen” gaze (“staring” phenomenon) and oro-alimentary automatisms. Ictal EEG patterns originating from occipital cortex correlate with lateralized clonic eyes and head twitching. In the case of parietal pattern, nonspecific motor activity is possible; sometimes, a child seems “listening” to his/her inner feelings. The above phenomena are contrary to a prevailing opinion that there is no clear clinical-electroencephalographic correlation of focal ictal patterns in infants and rather suggest the opposite.
As child grows, the amplitude of ictal activity tends to increase with growing involvement of the frontal lobes; many seizures become secondarily generalized. The phenomenon of secondary bilateral synchronization typically occurs after only a few weeks from the onset [1]. However, Gerard et al. [4] in the last observations found a delay of bilateral synchronization and additional foci of epileptiform activity generation, at least up to 2 months from the onset (possibly as antiepileptic drug effect) [4]. At this stage detection of early drug resistance may result to a wrong decision about surgical treatment. Extended video-EEG monitoring also has a considerable importance in this category of patients, because visualization of seizures originating from the same cortex area does not mean that all seizures originate only from this area [28].
Despite the various topographies, ictal EEG patterns of all episodes are very similar and correspond to rhythmic activity of the alpha or theta range, prone to the spread and involving all large cortex areas [7].
EEG in personal patients (n = 35) was characterized by diffuse slowing of background activity, while in the developed stage, background EEG was almost completely replaced by continuous ictal patterns. In the initial stages of the disease, interictal record revealed regional or multiregional epileptiform discharges with formation of multifocal independent spike foci (MISF) pattern. Most cases of MMPSI (20 patients, 57.1%) initially had MISF with transformation in MMPSI as frequency of epileptic seizures increased and migratory status developed. In seven cases (20%), monofocal epilepsy was initially observed, followed by addition of extra foci, new types of seizures, and increase of multifocal ictal events up to SE. At eight infants (22.9%), the first properly done EEG investigation fixed the multiregional SE pattern with its preservation in dynamic video-EEG studies and negative prognosis for live.
Ictal EEG patterns in the developed stage of MMPSI involved different areas of the cerebral cortex during a series of seizures, which could overlap each other in cases when ictal pattern in one area is not yet over, but the same pattern appeared in other cortical areas. There may be a complex picture, combining postictal changes in one region of the cerebral cortex, initial ictal pattern in another area, and developed ictal pattern in the third. Typical EEG pattern of MMPSI is presented in a series of electroencephalograms (Figures 1–7). In general, ictal pattern demonstrates migration of paroxysmal ictal characteristics from one region to another, without formation of stable interregional relations. Probably, only due to ictal pattern migration, patients are able to stay in SE of focal seizures for a long time without development of life-threatening cerebral edema.
Figure 1.
Patient G.E., 1 year old. Diagnosis: Malignant migrating partial seizures of infancy. EEG during status seizures. Emergence of regional ictal EEG pattern in the left frontal region in the form of fast epileptiform activity and transformation to regular activity of theta range with amplitude increase and sharp wave inclusion. In the left parietal, posterior temporal region is seen delta-accentuation after the previous seizure. Manifestation: Right-sided tonic seizure with oro-facial and versive components.
Figure 2.
The same patient. Continuation of ictal EEG. Ictal epileptiform activity involves neighboring regions and same areas of the right hemisphere, but with maintenance of left-sided lateralization. Manifestation: Bilateral tonic seizure.
Figure 3.
The same patient. Continuation of ictal EEG. Ictal epileptiform activity in the frontal areas changes to the right-sided lateralization. Manifestation: Transformation to asymmetric tonic seizure with left-sided accentuation.
Figure 4.
The same patient. Continuation of ictal EEG. Diffuse spread of ictal epileptiform activity with multiple spikes. On this background, emergence of regional accentuation of ictal pattern in the left parietal-posterior temporal region. Manifestation: Transformation to generalized tonic seizure with clonic component.
Figure 5.
The same patient. Continuation of ictal EEG. Slowing down of frequency characteristics of the diffuse ictal pattern with transformation to the delta slowing. In the opposite left parietal-posterior temporal region, activation of the regional ictal pattern with regionally accentuated polyspikes and spike-wave complexes is seen. Manifestation: Transformation to asymmetric tonic seizure with right-sided clonic component.
Figure 6.
The same patient. Continuation of ictal EEG. Shift of ictal pattern in the left parietal-posterior temporal region to the delta slowing with slow epileptiform complexes. At the same time in the right hemisphere, emergence of a new ictal pattern in the form of low-amplitude fast activity (lafa). Manifestation: Short-term decrease of clinical ictal severity.
Figure 7.
The same patient. Continuation of ictal EEG. Ictal pattern in the right hemisphere in the form of regular alpha-theta activity with frontal-central accentuation. Postictal changes in the left hemisphere in the form of depression of the bioelectric activity with delta rhythm dominance. Manifestation: Asymmetrical tonic seizure with left-sided accentuation.
The following variants of ictal patterns have been identified in patients with MMPSI: regional “saw tooth” activity of alpha and theta range; “lafa” runs were obligate ictal patterns and were detected at all patients with MMPSI; frequently runs of fast regular spike-wave complexes were also identified; and runs of slow regular spike-wave complexes (rarely), and diffuse spike- and polyspike-wave discharges.
Along with “classical” EEG pattern of MMPSI, atypical mixed variants were observed in the manner of superposition of continuous migratory multiregional SE pattern to suppression-burst pattern with diffuse polyspike-wave discharges (Figures 8–10). Five of these infants (three boys and two girls) had a special mixed form of epilepsy in the form of MMPSI combination with early myoclonic encephalopathy (EME) with the presence of multiple fragmented “erratic” myoclonus along with migrating focal status seizures.
Figure 8.
Patient P.S., age 1 year and 1 month old. Ictal EEG. Diagnosis: Mixed form of MMPSI + EME.
Figure 9.
The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal ictal patterns in the left centro-parietal area with central sagittal (vertex accent).
Figure 10.
The same patient. Continuation of ictal EEG. EEG reveals combination of suppression-burst pattern and focal ictal pattern in right occipital-posterior temporal area.
Such mixed form with transformation of EME into MMPSI was also described by specialists from the Department of Pediatrics of the Taipei City Hospital Zhongxing Branch (Taipei, Taiwan) in a female neonate [29].
4.2 Neuroimaging
According to the world literature, CT and MRI changes are absent, and the majority of MMPSI cases are regarded as cryptogenic. Atrophic changes are nonspecific and further are exacerbated by the constant epileptic seizures [1, 25].
Coppola et al. found left temporal lobe dual pathology in a child with MMRSI, including hippocampal sclerosis and cortical-subcortical blurring [23]. Caraballo et al. reported about mesial temporal lobe sclerosis in 3 of 17 patients [27]. Gross-Tsur et al. presented patients with MMPSI decreased N-acetyl aspartate in the frontal cortex and basal ganglia revealed by MR brain spectroscopy [30].
In cases of cryptogenic MMPSI, minimal or moderate subatrophic changes initially were fixed, sometimes in combination with a moderate delay of myelination, but with progressive cerebral atrophy at 11 children with persistent pharmacoresistant seizures. Dysgenetic brain malformations were found at neuroimaging only in two children with symptomatic analogs of MMPSI in the form of lissencephaly-pachygyria in one girl and polymicrogyria in another girl. Remaining ten patients with symptomatic analogs of MMPSI had a wide range of hypoxic-ischemic CNS lesions in the form of periventricular leukomalacia, parasagittal Chugani necrosis, and diffuse cortical-subcortical atrophy (“walnut” brain).
5. Treatment
MMPSI is a drug-resistant epilepsy form with serious prognosis. Treatment approaches are still developing. Baseline, old, and new antiepileptic drugs in various combinations, as well as corticosteroids, are ineffective [1, 2, 3]. However, Dulac observed seizure aggravation during treatment with carbamazepine and vigabatrin in these patients [3]. Perez et al. observed temporary seizure remission in two cases of MMPSI with combination of stiripentol (metabolic drug, inhibitor of several cytochrome P-450 enzymes) and high doses of clonazepam [31]. Hmaimess et al. published about effectiveness of levetiracetam in MMPSI [32]. Okuda et al. [5] reported efficacy of potassium bromide in migrating partial seizures of infancy. A 3-month-old boy and a 4-month-old girl with failure of common antiepileptic drugs reached complete remission of seizures in one case and significant decrease of seizure frequency (95%) in another case due to treatment with potassium bromide 80 mg/kg/day [5]. In all cases of seizure control, gradual improvement in psychomotor development of children was observed that also proves the leading role of epileptiform activity and persistent seizures in the development of epileptic encephalopathy [3].
Chien et al. have stopped erratic myoclonus and suppressive-burst pattern on EEG in a mixed form of EME + MMPSI using dextromethorphan 20 mg/kg [29].
There are different opinions about usefulness of ketogenic diet in MMPSI. So, François et al. proclaimed that seizures in MMPSI are also resistant to ketogenic diet [33]. But specialists from Children’s Neuroscience Centre of Royal Children’s Hospital (Parkville, Victoria, Australia) published data about efficacy of the ketogenic diet in children with this pharmacoresistant form of epilepsy [34].
Surgical treatment of MMPSI is unreasonable because of diffuse nature of brain damage and lack of clear local structural defect [3]. Theoretically, anterior callosotomy may be offered as a palliative intervention; however, there is no such experience in this form of epilepsy.
A group of scientists from the Pediatric Neurology Department of Azienda Ospedaliera Universitaria (Ancona, Italy) have published about positive experience of vagus nerve stimulation (VNS therapy) in three infants with pharmacoresistant MMPSI [35].
Our cases confirmed that MMPSI are resistant to antiepileptic therapy. Monotherapy had no significant effect in all patients. All patients with MMPSI failed to relieve from epileptic seizures. In 14 MMPSI cases, antiepileptic therapy was completely ineffective (56%), reduction of seizures >50% was observed in seven patients (28%), and only in six patients decrease of seizures was >75% (17.16%). Relatively effective combinations of antiepileptic drugs included valproates with barbiturates (phenobarbital and hexamidine) and benzodiazepines. Clobazam 1 mg/kg was most effective among benzodiazepine groups. In two patients positive effect was observed with combination of levetiracetam, and in one case – with combination of benzodiazepine and topiramate. Phenytoin in two cases caused moderate positive effect with “escape effect.” In one patient, frequency of seizures decreased during treatment with potassium bromide (50 mg/kg) but with side effects in the form of hypersomnia. High doses of vitamin B6 in two cases were moderately positive.
Ethosuximide, rufinamide, carbamazepine, and oxcarbazepine have no substantial positive effect. In one case, carbamazepine in cryptogenic focal frontal epilepsy with temporary positive effect caused subsequent aggravation of seizures with appearance of additional foci with clinical and electroencephalographic transformation into MMPSI.
Hormone therapy caused only a temporary moderate positive effect in eight cases and was completely ineffective at other cases.
For emergent relief of SE of hemiconvulsive and secondary generalized tonic-clonic seizures in 15 cases of MMPSI, benzodiazepines (relanium and midazolam) had only a temporary effect in eight or were completely ineffective in seven cases.
Positive effect in SE in MMPSI was observed with sodium oxybate administration at a dose of 100–150 mg/kg, 400 mg/min. This was done in seven cases of hemiconvulsive (n = 3) and secondary generalized tonic-clonic SE (n = 4) resistant to benzodiazepines with a temporary regression (six cases) or a decrease of clinical-EEG paroxysmal events (one case).
In three patients with MMPSI, intravenous valproates caused significant positive effect in relieving SE, especially in cases of tonic-autonomic seizures with episodes of apnea, with aggravation during treatment with benzodiazepines [36]. The recommended dose was 25 mg/kg intravenous over 5 min with the following maintenance infusion – 2 mg/kg/h.
Sodium thiopental (4 mg/kg for 2 min and then infusion of 0.2 mg/kg per minute) is the last chance to stop drug-resistant SE but caused death in one girl due to central inhibition of cardiac activity.
6. Prognosis
MMPSI is a form of epilepsy with poor prognosis. Within a few months after disease onset, frequency and duration of seizures increase up to the serial seizures and status epilepticus. A number of patients die in the first year of life due to multiple prolonged epileptic seizures, development of respiratory distress syndrome, and decorticate rigidity [30]. Based on the generalized clinical observations, mortality in this syndrome is 28% [3]. The results obtained by Marsh et al. are prognostically more favorable: during the 7-year follow-up, all six patients survived; however, psychomotor retardation with severe muscular hypotonia persisted in three of them, and only one patient reached seizure control for a long time [25].
Mortality at personal observed cases was 25.7% (n = 9); however, the expected mortality is higher due to short follow-up (1 year) in more than half of these patients. The oldest of the survived patients with MMPSI is 9 years old; there is gross delay of psychomotor development with unformed verticalization skills, absence of voice activity, spastic tetraparesis, and multiple focal asymmetric tonic, versive, pharyngo-oral, and dialeptic seizures.
Follow-up of patients with MMPSI allowed distinguishing the following subpopulations:
“Classical” form in the form of marked SE of migrating multifocal seizures is pharmacoresistant with a poor prognosis for psychomotor development, seizures, and life (19 cases, 54.3%).
Mixed form (MMPSI + EME) with a combination of electro-clinical MMPSI characteristics but also with the presence of fragmented “erratic” myoclonus and suppression-burst pattern with polyspike-wave discharges on EEG (five cases, 14.3%) with also poor prognosis for mental and motor functions, seizures, and life.
“Moderate” or “mild” form with a consistent evolution from unifocal form to multifocal form with EEG pattern MISF, and then developed expressed MMPSI electro-clinical characteristics, but with a possible regression and decrease in frequency of seizures during combined antiepileptic therapy (six cases, 17.1%).
“Subtle” form, in the form of only “subtle” minimal motor seizures, inhibitory seizures, multiple ictal patterns during sleep, and leading to awakening (five cases, 14.3%). This form causes a rough developmental delay in infants, but without video-EEG monitoring, it remains unrecognized [20].
7. Conclusions
MMPSI is an independent epileptic syndrome with special clinical-neurophysiological characteristics, distinct from other forms of epilepsy. Diagnosis can be established if there are different types of focal seizures, involving multiple extended EEG and electro-clinical ictal EEG patterns with involvement of several independent areas in both hemispheres. All the patients need complex investigations including dynamic video-EEG monitoring, neuroimaging, and genetic tests (whole-exome sequencing is more preferable).
MMPSI should also be differentiated from the syndrome described by Ohtahara – “severe epilepsy with multiple independent spike foci” (SE-MISF). In the literature, this form is also known as Markand-Blume-Ohtahara syndrome [37]. Unlike MMPSI, this form manifests with predominantly pseudogeneralized seizures: bilateral axial tonic spasms, atypical absences, and myoclonic but focal seizures could also observed. But SE-MISF and MMPSI could have evolutional changes into each other.
Therefore, malignant migrating partial seizures of infancy is the third type of infantile epileptic encephalopathy, along with early encephalopathies with suppression-burst pattern (Aicardi and Ohtahara syndromes) and West syndrome, when the cerebral cortex is more prone to generate epileptic excitation migrating from one area of the cortex to another, without clear interregional organization. This condition is caused by age-dependent features of infant brain with cortex hyperexcitability at a certain stage of evolution [3, 38].
The definition of this syndrome has not been defined in the international classification of epilepsies and epileptic syndromes. The term “malignant migrating partial seizures of infancy” characterizes this form of epilepsy rather as syndrome, so it is proposed to discuss the following title “malignant epilepsy of infancy with migrating multifocal seizures” that may more fully capture the essence of the disease. Taking into account contributions of scientists that first described this form of epilepsy (Coppola) and gave the most detailed description of the clinical and neurophysiological criteria (Dulac), the following definition is proposed: Coppola-Dulac syndrome [39].
Acknowledgments
I would like to express my special thanks to a veteran of World War II, the world’s famous coryphaeus of neurology and epileptology, Academician and Professor Vladimir Alexeevich Karlov; to an expert in epilepsy, President of the scientific council of the French Epilepsy Research Foundation, leading specialist of Children’s Hospital Necker, Professor Olivier Dulac; to my German teacher and mentor, Professor Hans Holthausen; to my scientific supervisors and epilepsy experts, Professor Konstantin Yurievich Mukhin and Professor Andrey Sergeevich Petrukhin; to the Head of the Department of Neurology, Neurosurgery and Medical Genetics of Pirogov Russian National Research Medical University, Professor Nikolay Nikolaevich Zavadenko; to the Head of the Department of Psychoneurology N2 of the Russian Children Clinical Hospital, Dr. Elena Stepanovna Il’ina; and to all my colleagues. Also, I would like to extend my special thanks to my big family and especially my wife Elena!
Conflict of interest
No conflict of interest.
\n',keywords:"malignant migrating partial seizures of infancy, Coppola-Dulac syndrome, status epilepticus in infancy, epileptic encephalopathy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/65033.pdf",chapterXML:"https://mts.intechopen.com/source/xml/65033.xml",downloadPdfUrl:"/chapter/pdf-download/65033",previewPdfUrl:"/chapter/pdf-preview/65033",totalDownloads:415,totalViews:0,totalCrossrefCites:0,dateSubmitted:"September 24th 2018",dateReviewed:"December 2nd 2018",datePrePublished:"December 31st 2018",datePublished:"November 13th 2019",dateFinished:null,readingETA:"0",abstract:"Malignant migrating partial seizures of infancy (MMPSI) is a rare and usually an unrecognized epileptic syndrome of infancy. The first publication was presented by Coppola and colleagues in 1995, and Dulac in 2005 summarized 24 patients’ follow-up in the Saint Vincent de Paul Hospital in Paris. Clinical cases have demonstrated a new epileptic syndrome, different from previously described forms of epileptic encephalopathies of infancy for the whole world of epileptology. Seizure onset before the age of 6 months but commonly start within a few weeks of birth. In the age of 1 to 10 months seizures become very frequent, polymorphic and usually get clustered nature; mental and motor retardation is clear observed. Clinical manifestation of seizures may include head and eyes version, lateralized clonic eyelid twitchings, fixed gaze, tonic tension or clonias of one limb or hemispasms, axial tonic spasms, chewing or sucking movements, episodes of apnea, flushing, hypersalivation, and secondary generalized seizures. MMPSI could be also considered as a special type of infantile status epilepticus. Video-EEG monitoring plays the most important role in the MMPSI diagnosis. Ictal EEG patterns involve different areas of the cerebral cortex of both hemispheres; initial zone of ictal patterns shifts from one region to another. MMPSI is a drug-resistant epilepsy with serious prognosis.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/65033",risUrl:"/chapter/ris/65033",signatures:"Alexey Kholin",book:{id:"7860",title:"Epilepsy",subtitle:"Advances in Diagnosis and Therapy",fullTitle:"Epilepsy - Advances in Diagnosis and Therapy",slug:"epilepsy-advances-in-diagnosis-and-therapy",publishedDate:"November 13th 2019",bookSignature:"Isam Jaber Al-Zwaini and Ban Adbul-Hameed Majeed Albadri",coverURL:"https://cdn.intechopen.com/books/images_new/7860.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"30993",title:"Prof.",name:"Isam Jaber",middleName:null,surname:"Al-Zwaini",slug:"isam-jaber-al-zwaini",fullName:"Isam Jaber Al-Zwaini"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"253091",title:"Dr.",name:"Alexey",middleName:null,surname:"Kholin",fullName:"Alexey Kholin",slug:"alexey-kholin",email:"drkholin@mail.ru",position:null,institution:{name:"Pirogov Russian National Research Medical University",institutionURL:null,country:{name:"Russia"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Etiology",level:"1"},{id:"sec_2_2",title:"2.1 Monogenic mutations with Mendelian type of inheritance",level:"2"},{id:"sec_2_3",title:"2.1.1 Early infantile epileptic encephalopathy type 3 (EIEE6; 609304)",level:"3"},{id:"sec_3_3",title:"2.1.2 Early infantile epileptic encephalopathy type 6 (EIEE6; 607208)",level:"3"},{id:"sec_4_3",title:"2.1.3 Early infantile epileptic encephalopathy type 13 (EIEE13; 614558)",level:"3"},{id:"sec_5_3",title:"2.1.4 Early infantile epileptic encephalopathy type 14 (EIEE14; 614959)",level:"3"},{id:"sec_6_3",title:"2.1.5 Early infantile epileptic encephalopathy type 16 (EIEE14; 615338)",level:"3"},{id:"sec_7_3",title:"2.1.6 Progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA; 615760)",level:"3"},{id:"sec_8_3",title:"2.1.7 Rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222765)",level:"3"},{id:"sec_10_2",title:"2.2 Chromosome aberrations",level:"2"},{id:"sec_11_2",title:"2.3 Other etiological factors",level:"2"},{id:"sec_13",title:"3. Clinical signs",level:"1"},{id:"sec_14",title:"4. Electroencephalographic findings and neuroimaging",level:"1"},{id:"sec_14_2",title:"4.1 EEG and video-EEG monitoring",level:"2"},{id:"sec_15_2",title:"4.2 Neuroimaging",level:"2"},{id:"sec_17",title:"5. Treatment",level:"1"},{id:"sec_18",title:"6. Prognosis",level:"1"},{id:"sec_19",title:"7. Conclusions",level:"1"},{id:"sec_20",title:"Acknowledgments",level:"1"},{id:"sec_23",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: A malignant disorder with developmental arrest. Epilepsia. 1995;36(10):1017-1024'},{id:"B2",body:'Coppola G. Malignant migrating partial seizures in infancy: An epilepsy syndrome of unknown etiology. Epilepsia. 2009;50(Supp. 5):49-51. DOI: 10.1111/j.1528-1167.2009.02121.x'},{id:"B3",body:'Dulac O. Malignant migrating partial seizures in infancy. In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, editors. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. John Libbey; 2005. pp. 73-76. ISBN: 2-7420-0575-7'},{id:"B4",body:'Gerard F, Kaminska A, Plouin P, Echenne B, Dulac O. Focal seizures versus focal epilepsy in infancy: A challenging distinction. Epileptic Disorders. 1999;1(2):135-139'},{id:"B5",body:'Okuda K, Yasuhara A, Kamei A, Araki A, Kitamura N, Kobayashi Y. Successful control with bromide of two patients with malignant migrating partial seizures in infancy. Brain & Development. 2000;22(1):56-59'},{id:"B6",body:'Veneselli E, Perrone MV, Di Rocco M, Gaggero R, Biancheri R. Malignant migrating partial seizures in infancy. Epilepsy Research. 2001;46(1):27-32'},{id:"B7",body:'Panayiotopoulos CP. A Clinical Guide to Epileptic Syndromes and their Treatment. Bladon Medical Publishing. Oxford, 2002. pp. 36-49. 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Gene. 2013;531:467-471. DOI: 10.1016/j.gene.2013.08.096'},{id:"B16",body:'Kawasaki Y, Kuki I, Ehara E, Murakami Y, Okazaki S, Kawawaki H, et al. Three cases of KCNT1 mutations: Malignant migrating partial seizures in infancy with massive systemic to pulmonary collateral arteries. The Journal of Pediatrics. 2017;191:270-274. DOI: 10.1016/j.jpeds.2017.08.057'},{id:"B17",body:'Madaan P, Jauhari P, Gupta A, Chakrabarty B, Gulati S. A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures. Brain & Development. 2018;40(3):229-232. DOI: 10.1016/j.braindev.2017.09.008'},{id:"B18",body:'Milh M, Falace A, Villeneuve N, Vanni N, Cacciagli P, Assereto S, et al. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Human Mutation. 2013;34:869-872. DOI: 10.1002/humu.22318'},{id:"B19",body:'Zhang X, Ling J, Barcia G, Jing L, Wu J, Barry BJ, et al. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. American Journal of Human Genetics. 2014;94(4):547-558. DOI: 10.1016/j.ajhg.2014.03.003'},{id:"B20",body:'Kholin AA. The syndrome of malignant migrating partial seizures in infancy or Coppola-Dulac syndrome (19 cases). Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova. 2013;113(3):21-27'},{id:"B21",body:'Bedoyan JK, Kumar RA, Sudi J, Silverstein F, Ackley T, Iyer RK, et al. Duplication 16p11.2 in a child with infantile seizure disorder. American Journal of Medical Genetics Part A. 2010;152A(6):1567-1574. DOI: 10.1002/ajmg.a.33415'},{id:"B22",body:'Poduri A, Chopra SS, Neilan EG, Elhosary PC, Kurian MA, Meyer E, et al. Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy. Epilepsia. 2012;53(8):e146-e150. DOI: 10.1111/j.1528-1167.2012.03538.x'},{id:"B23",body:'Coppola G, Operto FF, Auricchio G, D’Amico A, Fortunato D, Pascotto A. Temporal lobe dual pathology in malignant migrating partial seizures in infancy. Epileptic Disorders. 2007;9(2):145-148. DOI: 10.1684/epd.2007.0106'},{id:"B24",body:'Kholin AA. Status epilepticus in infancy and early childhood. D.M.thesis. Moscow. 2010. 54 p'},{id:"B25",body:'Marsh E, Melamed SE, Barron T, Clancy RR. Migrating partial seizures in infancy: Expanding the phenotype of a rare seizure syndrome. Epilepsia. 2005;46(4):568, 72. DOI: 10.1111/j.0013-9580.2005.34104.x'},{id:"B26",body:'Dulac O, Chiron C. Malignant epileptic encephalopathies in children. Baillière’s Clinical Neurology. 1996;5(4):765-781'},{id:"B27",body:'Caraballo RH, Fontana E, Darra F, Cassar L, Negrini F, Fiorini E, et al. Migrating focal seizures in infancy: Analysis of the electroclinical patterns in 17 patients. Journal of Child Neurology. 2008;23(5):497-506. DOI: 10.1177/0883073807309771'},{id:"B28",body:'Kholin AA, Ilina ES, Kolpakchi LM, Fedonuk ID, Mikhailova SV, Semykina LI, et al. Malignant migrating partial seizures in infancy. Clinical observation of 6 cases. Rus. zh. detsk. nevrol. 2007;2(2):25-38'},{id:"B29",body:'Chien YH, Lin MI, Weng WC, Du JC, Lee WT. Dextromethorphan in the treatment of early myoclonic encephalopathy evolving into migrating partial seizures in infancy. Journal of the Formosan Medical Association. 2012;111(5):290-294. DOI: 10.1016/j.jfma.2012.03.007'},{id:"B30",body:'Gross-Tsur V, Ben-Zeev B, Shalev RS. Malignant migrating partial seizures in infancy. Pediatric Neurology. 2004;31(4):287-290. DOI: 10.1016/j.pediatrneurol.2004.05.001'},{id:"B31",body:'Perez J, Chiron C, Musial C, Rey E, Blehaut H, d\'Athis P, et al. Stiripentol: Efficacy and tolerability in epileptic children. Epilepsia. 1999;40(11):1618-1612'},{id:"B32",body:'Hmaimess G, Kadhim H, Nassogne MC, Bonnier C, van Rijckevorsel K. Levetiracetam in a neonate with malignant migrating partial seizures. Pediatric Neurology. 2006;34(1):55-59. DOI: 10.1016/j.pediatrneurol.2005.06.011'},{id:"B33",body:'François LL, Manel V, Rousselle C, David M. Ketogenic regime as anti-epileptic treatment: Its use in 29 epileptic children. Archives de Pédiatrie. 2003;10(4):300-306'},{id:"B34",body:'Thammongkol S, Vears DF, Bicknell-Royle J, Nation J, Draffin K, Stewart KG, et al. Efficacy of the ketogenic diet: Which epilepsies respond? Epilepsia. 2012;53(3):e55-e59. DOI: 10.1111/j.1528-1167.2011.03394.x'},{id:"B35",body:'Zamponi N, Rychlicki F, Corpaci L, Cesaroni E, Trignani R. Vagus nerve stimulation (VNS) is effective in treating catastrophic 1 epilepsy in very young children. Neurosurgical Review. 2008;31(3):291, 7. DOI: 10.1007/s10143-008-0134-8'},{id:"B36",body:'Kholin AA, Ilina ES, Lemeshko ID, Mukhin KY, Petrukhin AS. Malignant migrating partial seizures of infancy: The experience of treatment of status epilepticus in infancy using intravenous valproate – Convulex (a clinical cases). Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova. 2010;110(3 Supp. 2):17-24'},{id:"B37",body:'Yamatogi Y, Ohtahara S. Severe epilepsy with multiple independent spike foci. Journal of Clinical Neurophysiology. 2003;20(6):442-448'},{id:"B38",body:'Ohtahara S, Yamatogi Y. Epileptic encephalopathies in early infancy with suppression – Burst. Journal of Clinical Neurophysiology. 2003;20(6):398-407'},{id:"B39",body:'Kholin AA. Malignant migrating partial seizures in infancy or Coppola-Dulac syndrome. Materials of 29th International Epilepsy Congress, Rome. 2011. p. 716'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Alexey Kholin",address:"drkholin@mail.ru",affiliation:'
Department of Neurology, Neurosurgery and Medical Genetics of Pediatric Faculty, Pirogov Russian National Research Medical University, Moscow, Russia
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Gorbunov is currently Research Associate Professor with the Henry M. Jackson Foundation for the Advancement of Military Medicine in Bethesda, Maryland. Dr. Gorbunov received his Ph.D. from the Russian Academy Sciences in St. Petersburg, Russia. He then completed a two-year postdoctoral training in Biomedicine at the Research Center of the Consorzio \\Mario Negri\\ Sud (Italy) and a two-year DOE postdoctoral training program in Radiation Sciences at the University of Pittsburgh, Graduate School of Public Health. Pittsburgh, Pennsylvania. In 1994 and 2000 Dr. Gorbunov was a recipient of the National Research Council Fellowship Awards to pursue the NRC Senior Research Associateship at the Walter Reed Army Institute of Research (WRAIR). A long-term interest is the tissue barrier homeostasis in traumatic injury, inflammation, stress, and immunosuppression. 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IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. We uphold a flexible Copyright Policy, guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Monograph",metaDescription:"IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.",metaKeywords:null,canonicalURL:"/page/publication-agreement-monograph",contentRaw:'[{"type":"htmlEditorComponent","content":"
When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
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CORRESPONDING AUTHOR'S GRANT OF RIGHTS
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Subject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
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An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use the Monograph/Compact in whole, partial or adapted form and/or incorporated in, or in conjunction with, other works, in electronic and print editions of the Publication and in derivative works, and on any platform owned and/or operated by IntechOpen throughout the world, in all languages, and in all media and formats now known, or later developed.
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An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Work, including the right to deposit the Work in open access digital repositories.
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An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Work in whole, partial, or adapted from and/or incorporated in, or in conjunction with, other works under the condition that the Author and Co-Authors are attributed (currently this is carried out by publishing the Work under a Creative Commons Attribution-NonCommercial 4.0 International License).
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The foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
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The Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
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The Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
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Subject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
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Subject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
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All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
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The Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
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AUTHOR'S DUTIES
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When distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
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The Author agrees to:
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Define the topic and title of the Work.
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Submit the complete manuscript; the Author assumes the responsibility for the published content, defining the sections of the Work and structuring the content and writing a foreword i.e. the introductory chapter of the Work.
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Submit all the corrections in due time.
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The Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
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All payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
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The Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
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The Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
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The Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
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AUTHOR'S WARRANTY
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The Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
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The Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
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The Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
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The Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
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Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
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TERMINATION
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IntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
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In the event of termination, IntechOpen will notify the Author of the decision in writing.
\\n\\n
IntechOpen’s DUTIES AND RIGHTS
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Unless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
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Unless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
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IntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
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IntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n
IntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
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MISCELLANEOUS
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Further Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n
Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
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Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
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Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
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Variation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
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Severance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
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No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
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Governing law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\n
CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n
Subject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
\n\n
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to publish, communicate to the public, reproduce, republish, transmit, sell, distribute and otherwise use the Monograph/Compact in whole, partial or adapted form and/or incorporated in, or in conjunction with, other works, in electronic and print editions of the Publication and in derivative works, and on any platform owned and/or operated by IntechOpen throughout the world, in all languages, and in all media and formats now known, or later developed.
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to create and store electronic archival copies of the Work, including the right to deposit the Work in open access digital repositories.
\n\t
An irrevocable, worldwide, royalty-free, perpetual, transferable, sublicensable, non-exclusive right to license others to reproduce, translate, republish, transmit and distribute the Work in whole, partial, or adapted from and/or incorporated in, or in conjunction with, other works under the condition that the Author and Co-Authors are attributed (currently this is carried out by publishing the Work under a Creative Commons Attribution-NonCommercial 4.0 International License).
\n
\n\n
The foregoing licenses shall survive the expiry or termination of this Publication Agreement for any reason.
\n\n
The Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\n
The Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\n
Subject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
\n\n
Subject to the license granted above, the Author and Co-Authors retain patent, trademark and other intellectual property rights to the Work.
\n\n
All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\n
The Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
\n\n
AUTHOR'S DUTIES
\n\n
When distributing or re-publishing the Work, the Author agrees to credit the Monograph/Compacts as the source of first publication, as well as IntechOpen. The Author guarantees that Co-Authors will also credit the Monograph/Compacts as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Work.
\n\n
The Author agrees to:
\n\n
\n\t
Define the topic and title of the Work.
\n\t
Submit the complete manuscript; the Author assumes the responsibility for the published content, defining the sections of the Work and structuring the content and writing a foreword i.e. the introductory chapter of the Work.
\n\t
Submit all the corrections in due time.
\n
\n\n
The Author will be held responsible for the payment of the agreed Open Access Publishing Fee before the completion of the project (Monograph/Compacts publication).
\n\n
All payments shall be due 30 days from the date of issue of the invoice. The Author or whoever is paying on behalf of the Author and Co-Authors will bear all banking and similar charges incurred.
\n\n
The Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Work worldwide for the full term of the above licenses, and shall provide to IntechOpen, at its request, the original copies of such consents for inspection or the photocopies of such consents.
\n\n
The Author shall obtain written informed consent for publication from those who might recognize themselves or be identified by others, for example from case reports or photographs.
\n\n
The Author shall respect confidentiality during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Author and Co-Authors are confidential and are intended only for the recipients. The contents of any communication may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n
AUTHOR'S WARRANTY
\n\n
The Author and Co-Authors confirm and warrant that the Work does not and will not breach any applicable law or the rights of any third party and, specifically, that the Work contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy.
\n\n
The Author and Co-Authors confirm that: (i) the Work is their original work and is not copied wholly or substantially from any other work or material or any other source; (ii) the Work has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) Authors and any applicable Co-Authors are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) Authors and any applicable Co-Authors have not assigned, and will not during the term of this Publication Agreement purport to assign, any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\n
The Author and Co-Authors also confirm and warrant that: (i) he/she has the power to enter into this Publication Agreement on his or her own behalf and on behalf of each Co-Author; and (ii) has the necessary rights and/or title in and to the Work to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licences in this Publication Agreement. If the Work was prepared jointly by the Author and Co-Authors, the Author confirms that: (i) all Co-Authors agree to the submission, license and publication of the Work on the terms of this Publication Agreement; and (ii) the Author has the authority to enter into this biding Publication Agreement on behalf of each Co-Author. The Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each Co-Author.
\n\n
The Author agrees to indemnify IntechOpen harmless against all liabilities, costs, expenses, damages and losses, as well as all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of, or in connection with, any breach of the agreed confirmations and warranties. This indemnity shall not apply in a situation in which a claim results from IntechOpen's negligence or willful misconduct.
\n\n
Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n
TERMINATION
\n\n
IntechOpen has the right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Author and/or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Author and/or any Co-Author (being a private individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Author and/or any Co-Author (as a corporate entity) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for, or enters into, any compromise or arrangement with any of its creditors.
\n\n
In the event of termination, IntechOpen will notify the Author of the decision in writing.
\n\n
IntechOpen’s DUTIES AND RIGHTS
\n\n
Unless prevented from doing so by events beyond its reasonable control, IntechOpen, at its discretion, agrees to publish the Work attributing it to the Author and Co-Authors.
\n\n
Unless prevented from doing so by events beyond its reasonable control, IntechOpen agrees to provide publishing services which include: managing editing (editorial and publishing process coordination, Author assistance); publishing software technology; language copyediting; typesetting; online publishing; hosting and web management; and abstracting and indexing services.
\n\n
IntechOpen agrees to offer free online access to readers and use reasonable efforts to promote the Publication to relevant audiences.
\n\n
IntechOpen is granted the authority to enforce the rights from this Publication Agreement on behalf of the Author and Co-Authors against third parties, for example in cases of plagiarism or copyright infringements. In respect of any such infringement or suspected infringement of the copyright in the Work, IntechOpen shall have absolute discretion in addressing any such infringement that is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n
IntechOpen has the right to include/use the Author and Co-Authors names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Work and has the right to contact the Author and Co-Authors until the Work is publicly available on any platform owned and/or operated by IntechOpen.
\n\n
MISCELLANEOUS
\n\n
Further Assurance: The Author shall ensure that any relevant third party, including any Co-Author, shall execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n
Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n
Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by, or on behalf of, the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (known as the "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of any fraudulent pre-contract misrepresentation or concealment.
\n\n
Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n
Variation: No variation of this Publication Agreement shall have effect unless it is in writing and signed by the parties, or their duly authorized representatives.
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Severance: If any provision, or part-provision, of this Publication Agreement is, or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted. Any modification to, or deletion of, a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n
No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Author or any Co-Author, nor authorize any party to make or enter into any commitments for, or on behalf of, any other party.
\n\n
Governing law: This Publication Agreement and any dispute or claim, including non-contractual disputes or claims arising out of, or in connection with it, or its subject matter or formation, shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of, or in connection with, this Publication Agreement, including any non-contractual disputes or claims.
\n\n
Policy last updated: 2018-09-11
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